Next Article in Journal
Regenerating Gene Protein as a Novel Autoantigen in the Pathogenesis of Sjögren’s Syndrome
Previous Article in Journal
Antibody Reactivity of B Cells in Lupus Patients with Increased Disease Activity and ARID3a Expression
Previous Article in Special Issue
Reverse Signaling Contributes to Control of Chronic Inflammation by Anti-TNF Therapeutics
Open AccessReview

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

Department of Molecular Neurobiology, Faculty of Mathematics and Natural Sciences, University of Groningen, Groningen 9747 AG, The Netherlands
Department of Neurology and Alzheimer Research Center, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, The Netherlands
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA), Antwerp 2020, Belgium
Laboratory of Neurochemistry and Behavior, Biobank, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium
University Center of Psychiatry & Interdisciplinary Center of Psychopathology of Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, The Netherlands
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Olaf Maier
Antibodies 2015, 4(4), 369-408;
Received: 15 September 2015 / Revised: 23 October 2015 / Accepted: 11 November 2015 / Published: 19 November 2015
(This article belongs to the Special Issue TNF in the Regulation of Immune Cells)


Numerous studies have revealed the pleiotropic functions of tumor necrosis factor alpha (TNF-α), and have linked it with several neurodegenerative disorders. This review describes the signaling pathways induced by TNF-α via its two receptors (TNFR1 and TNFR2), and their functions in neurodegenerative processes as in Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and ischemic stroke. It has become clear that TNF-α may exert divergent actions in neurodegenerative disorders, including neurodegenerative and neuroprotective effects, which appear to depend on its signaling via either TNFR1 or TNFR2. Specific targeting of these receptors is a promising therapeutic strategy for many disorders.
Keywords: tumor necrosis factor alpha (TNF-α); TNFR1; TNFR2; TNFR signaling pathways; neurodegenerative disorders; therapy tumor necrosis factor alpha (TNF-α); TNFR1; TNFR2; TNFR signaling pathways; neurodegenerative disorders; therapy

1. Introduction

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine implicated in multiple inflammatory diseases, including cancer, rheumatoid arthritis, and in neurodegeneration as in Alzheimer’s disease (AD), stroke, multiple sclerosis (MS), and Parkinson’s disease (PD) [1,2,3,4,5]. TNF-α is synthesized as a type II transmembrane protein of 26 kDa and forms a stable homo-trimeric molecule (mTNF-α) to exert its pleiotropic biological activities. It can be processed by proteolytic cleavage via TNF-α converting enzyme (TACE/ADAM17) to a 17 kDa monomeric protein, which is biologically active as a soluble homo-trimeric molecule of 51 kDa (sTNF-α). TNF-α induces various cellular responses through its interaction with two distinct transmembrane receptors, the 55 kDa TNF receptor type I (TNFR1) and the 75 kDa TNF receptor type II (TNFR2). Under normal physiological conditions, TNFR1 is ubiquitously expressed in various cell types and tissues, whereas TNFR2 is predominantly expressed at low levels in immune cells and endothelial cells [6,7,8,9]. TNFR1 activation can be induced by either sTNF-α or mTNF-α, and TNFR2 activation is predominantly initiated by mTNF-α [10]. TNF-α is classically known to exert pro-apoptotic functions via TNFR1 [11] and via TNFR2 in co-operation with TNFR1 [12,13]. On the contrary, more recent evidence clearly indicates that TNF-α induces cell survival and cellular proliferation via its TNFR2 [14,15]. This led to new insights that TNF-α exerts opposing effects via its two receptors with respect to neurodegeneration and neuroprotection. The potent pro-inflammatory functions of TNF-α in the brain play an important role in the etiology of neurodegenerative disorders such as ischemia/ischemic stroke, MS, and AD [14,16,17,18]. Therefore, a thorough understanding of TNF-α signaling pathways in neurodegenerative disorders can promote the development of effective agents in the treatment of these conditions.
This review will discuss TNF-α-mediated functions in the healthy and unhealthy central nervous system (CNS), focusing on TNF-α-mediated signaling pathways via its receptors, TNFR1 and TNFR2. Finally, we will examine these signaling pathways as potential therapeutic strategies for neurodegenerative disorders, focusing on AD, PD, ischemic stroke, and MS.

2. TNF-α Receptor Signaling Pathways

2.1. TNF-α Receptor 1 Signaling

The two distinct transmembrane receptors of TNF-α are characterized by a conserved domain of N-terminal repeating cysteine-rich motif in extracellular regions that specifically interact with diverse TNF-related ligands [19]. The conserved domain is necessary and sufficient for the preassembly of TNFR complexes that bind TNF-α trimers and mediate downstream signaling [20]. However, the intracellular domains of the two receptors lack homologous sequences [21], suggesting that distinct signaling pathways emanate from the two receptors. TNFR1 is distinguished from TNFR2 by its intracellular death domains (DDs) [22]. The extracellular domain of TNFR1 contains a well-ordered cysteine-rich amino-terminal, known as the preligand binding assembly domain (PLAD). PLAD favors pre-assembly of TNFR1 into trimeric complexes and functions as a preventative measure for receptor auto-activation and is essential for ligand binding [23]. TNFR1 can be activated by both sTNF-α and mTNF-α [10]. TNFR1-induced apoptosis involves formations of two sequential signal complexes (complex I and complex II) that are separated both temporally and spatially, but is limited by the successful activation of complex I [24]. After TNF-α binding, the activated TNFR1 acts via its intracellular DDs to recruit the core adaptor TNFR-associated death domain (TRADD) [25,26,27]. Furthermore, receptor-interacting protein 1 (RIP1) is recruited rapidly and modified with non-degradative poly-ubiquitin chains [28,29]. TRADD subsequently recruits other proteins such as TNFR-associated factor 2 (TRAF2) [30], inhibitor of apoptosis protein 1 (cIAP1), and inhibitor of apoptosis protein 2 (cIAP2) [31], forming the initial signaling complex I. This signaling complex with RIP1 ubiquitination initiates the later activation of the catalytic IκB kinase (IKK) complex [32]. The activated IKK complex, which consists of an IKKα subunit and an IKKβ subunit, functions as an essential regulatory subunit of the IKK complex (IKKγ/NEMO), which subsequently phosphorylates the inhibitor of the kappa-B (IκB) complex [33]. The IκB complex is then degraded via the ubiquitin-proteasome. Consequently, NF-κB composed of p50/p52 and RelA (p65)/RelB subunits is released and translocated into the nucleus to initiate the transcription of anti-apoptotic genes, cIAP-1, cIAP-2, TRAF1, TFAF2 as well as cellular FLICE-like inhibitory protein (cFLIP), to inhibit caspase 8 release from complex II [30,32,34,35,36] (Figure 1). The caspase-8 inhibitor cFLIP(L), which is harbored in complex II, simultaneously inhibits the release of pre-caspase 8 [24,34].
When complex I signaling fails to activate the NF-κB pathway in some instances, the activated TNFR1 will recruit complex II to trigger apoptotic processing (Figure 1). After ligand binding to TNFR1, the silencer of DDs is dissociated from the intracellular domains of TNFR1, and recruits the adaptor proteins such as TRADD, RIP1, TRAF2, and Fas-associated death domain (FADD) and pre-caspase 8 to form complex II [35]. In the activated complex, FADD triggers pre-caspase 8 activation, resulting in the release of p18/p12 fragments that can trigger downstream caspase cascades to participate in apoptotic processes [24]. This pro-apoptotic signaling mechanism involves FADD and caspase 8 as the key factors to trigger apoptosis [36,37]. Upon recruitment of FADD and caspase-8, initiation of apoptosis via caspase-8 is mainly determined by levels of the anti-apoptotic protein cFLIP(L) [38]. NF-κB activation triggered by complex I signaling determines the availability of the cFLIP(L) protein at the moment complex II is formed [38]. Therefore, adequate production of cFLIP(L) via NF-κB upon complex I signaling prevents subsequent caspase-8-mediated apoptosis of the complex II signaling pathway [39].
TNFR1 signaling can also trigger caspase-independent programmed necrosis (necroptosis) in Jurkat cells and in ischemic brain injury [40,41,42]. It was shown in mouse embryonic TNFR1−/− fibroblast cells that necrotic cell death is primarily dependent on TNFR1-mediated pathways [43]. In this process, RIPs, FADD, and TRAF2 elements are still the critical components to form complex IIb [43] (Figure 1). RIP1 is required for the formation of complex IIb [44]. Additionally, RIP3 assembly is essential for RIP1 recruitment to this complex and is identified as a crucial kinase to phosphorylate RIP1, which in turn phosphorylates RIP3 to form the RIP1-RIP3 pre-necrotic complex [45]. This activated complex phosphorylates the downstream mixed lineage kinase domain-like protein (MLKL) which subsequently triggers necrosis [46]. MLKL is therefore a critical factor in RIP3-mediated downstream necroptotic pathways. Dephosphorylation of RIP3 via protein phosphatase 1B (Ppm1b) restricts necroptosis [47]. In addition to caspase suppression, cFLIP proteins can potentially inhibit TNF-induced necroptosis [48]. Necroptosis is a newly discovered pathway of cell death with essential functions in tissue homeostasis and development, and is particularly studied in cancers and skin diseases. However, research on this pathway remains rather limited in CNS conditions. In primary hippocampal neurons, necroptosis was induced via RIP3 upon an ischemic insult [49]. Moreover, it was recently shown in vivo in mice that intracerebroventricular injection with TNF-α caused RIP3-mediated necroptosis of hippocampal neurons [50]. Besides neurons, necroptosis can also occur in activated (by stimulation with different inflammatory stimuli, including TNF-α) primary microglia upon the inhibition of caspase-8 [51]. Interestingly, in mixed cultures (where also primary neurons and astrocytes were present), necroptosis of activated microglia protected neurons from cell death [51]. Yuan’s group [52] reported that necroptosis in cortical neurons mainly depends on the RIP1-RIP3-MLKL signaling pathway induced via TNF-α/TNFR1 in MS. Przedborski’s group [53], however, showed that necroptosis-driven death of motor neurons triggered by amyotrophic lateral sclerosis (ALS) involves the RIP1-MLKL signaling pathway independent of TNF signaling. As such, it seems that RIP1-MLKL-mediated neuronal necroptosis may be induced in different ways, both dependent or independent of TNF-α.
Figure 1. Multiple forms of TNFR1 signaling activation are mediated through intracellular protein complex assembly. The trimeric TNF-α engagement of TNFR1 leads to cellular apoptosis or cell survival via the distinct complex signaling pathways.
Figure 1. Multiple forms of TNFR1 signaling activation are mediated through intracellular protein complex assembly. The trimeric TNF-α engagement of TNFR1 leads to cellular apoptosis or cell survival via the distinct complex signaling pathways.
Antibodies 04 00369 g001

2.2. TNF-α Receptor 2 Signaling

Compared to TNFR1-mediated pathways, TNFR2-mediated signaling is still less well understood. TNFR2 is typically expressed at a low level in cells of the immune system, and is activated primarily by mTNF-α [10]. Unlike TNFR1, TNFR2 does not include a death domain (DD). Trimerization of TNFR2 is induced upon binding of mTNF-α, leading to the recruitment of TRAF2 to the intracellular TRAF binding motif, which subsequently causes the recruitments of TRAF1, cIAP1, and cIAP2 [54] (Figure 2). TRAF2 is a key mediator in this signaling pathway that triggers the subsequent signaling cascades leading to activation of NF-κB [55]. The activation TRAF2-cIAP1/2 complex is recruited to NF-κB-inducing kinase (NIK) by TRAF3, resulting in proteosomal degradation of NIK [56]. TNFR2 activation by mTNF-α maintains NIK stabilization via induction of TRAF3 degradation, and thereby activates IκBα, leading to phosphorylation and activation of IKKα. Phosphorylated IKKα consequently activates the NF-κB precursor protein p100 [57]. This noncanonical NF-κB activation is independent of IKKβ and IKKγ [56]. Moreover, it has been reported that human TNFR2 contains a second intracellular binding region for TRAF2 and that this intracellular region can recruit TRAF2, which leads to the activation of NF-κB, dependent on activation of NIK and IκBα. Deletion of this binding region impairs the ability of TNFR2 to activate NF-κB [58].
TNFR2-mediated activation of NF-κB can also occur via the phosphoinositide 3-kinases (PI3K)-protein kinase B/serine-threonine kinase (PKB/Akt) signaling pathway [59] (Figure 2). The phosphorylated IκB is degraded via the ubiquitin-proteasome and NF-κB is translocated into the nucleus to initiate transcription [60]. TNFR2-mediated NF-κB activation is downregulated by phosphatase and the tensin homolog deleted on chromosome 10 (PTEN), which is a strong inhibitor of the PI3K-PKB/Akt pathway. However, NF-κB activation via TNF-α leads to downregulation of PTEN [61].
In addition to NF-κB activation, signaling via TNFR2 can elicit various non-apoptotic responses including c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinases (MAPK) that depend on the recruitment of TRAF2 to the different intracellular binding sites of TNFR2 [54,62]. In these signaling pathways, TNFR2 binds TRAF2 to its intracellular region, and subsequently recruits TRAF1, TRAF3, cIAP1, and cIAP2 [63,64]. According to spatial and temporal separation, this complex binds to a MAPK kinase kinase (MAP3K) protein called MEKK1 and enhances the activity of this kinase and the phosphorylation of JNK-activating kinase (JNKK1) [65], and thereby stimulates JNK activation to promote downstream signaling pathways which mediate cell survival. It should be noted, however, that while acute activation of JNK via TRAF2 has been related to cell survival, prolonged activation may also lead to apoptosis [66,67,68]. TNF-α-mediated JNK activation depends at least in part on MEKK1 [62,65]. As opposed to TRAF1 and TRAF3, TRAF2 positively regulates JNK activation [55]. It has been suggested that TNFR2 harbors two sequences that are adaptors specific for JNK signaling [69]. TNFR2-TRAFs/cIAPs can mediate activation of the p38 MAPK signaling pathway. TRAF2 is a major player to promote activation of the p38 MAPK signaling pathway [70]. In this pathway, the TRAFs/cIAPs complex recruits RIP and subsequently activates MKK3 to initiate p38 MAPK activation [27,71,72].
TRAF2, TRAF1, and cIAP play a pivotal role not only in TNFR1 signaling pathways but also in TNFR2 pathways. This implicates that there could be a crosstalk between the two receptors [73]. It has been demonstrated that the depletion of TRAF2 induced by TNFR2 activation specifically accelerates the TNFR1-dependent caspase 8 activation [74,75,76]. TNFR2 signaling in a certain circumstance may therefore enhance TNFR1-mediated apoptosis by caspase 8 activation. Crosstalk between TNFR1 and TNFR2 is complicated and dependent on the physiologic environment and signaling kinetics between the two receptors. We have previously described TNFR crosstalk in [73].
Figure 2. Multiple forms of TNFR2 signaling activation are mediated through intracellular protein complex assembly. The transmembrane trimeric TNF-α engagement of TNFR2 leads to cellular survival via the distinct complex signaling pathways. PKB/Akt signaling is described in [59,73].
Figure 2. Multiple forms of TNFR2 signaling activation are mediated through intracellular protein complex assembly. The transmembrane trimeric TNF-α engagement of TNFR2 leads to cellular survival via the distinct complex signaling pathways. PKB/Akt signaling is described in [59,73].
Antibodies 04 00369 g002

3. TNF and Its Receptors—Involvement in Neurodegenerative Disorders

3.1. Alzheimer’s Disease

AD is a progressive neurodegenerative disorder, and the most common cause of dementia [77]. Besides the well-known pathological hallmarks of AD, including the formation of toxic aggregates of amyloid beta (Aβ) and hyperphosphorylated tau proteins, neuroinflammation was more recently described to play a fundamental role in the pathophysiological processes of AD, in which TNF-α in particular could be an important mediator [78] (also see Table 1). Evidence for the involvement of TNF-α in AD emanates from various research disciplines. On a genetic level, multiple polymorphisms in the TNF-α gene may be associated with the risk of developing AD [79]. For example, the TNF-α G308A promoter polymorphism, which may cause higher TNF-α expression levels, has been found to increase the risk of AD in certain populations [80,81,82]. At the protein level, plasma and serum TNF-α protein levels are elevated in AD [83,84,85]. Moreover, TNF-α levels in AD brain tissue were found to be increased, originating from microglia surrounding Aβ plaques [86,87,88]. Besides promoting ongoing pro-inflammatory processes in the AD brain, increased TNF-α levels can also affect the accumulation of Aβ. For example, it has been suggested that higher levels of pro-inflammatory cytokines may interfere with phagocytosis of fibrillar Aβ via mechanisms that need further clarification [89]. Yet, in monocyte-derived macrophages, it was shown that cytokines, including TNF-α, could directly decrease the expression of mediators involved in the degradation of aggregated proteins, such as insulin degrading enzyme, thereby interfering with the breakdown of fibrillary Aβ [90]. Moreover, TNF-α may increase Aβ production by enhancing beta-secretase (BACE1) expression (via NF-κB-dependent pathways) and activity and stimulating gamma-secretase activity via JNK-dependent MAPK signaling [91,92].
The extents of signaling through TNFR1 and TNFR2 are an important aspect to consider when interpreting the role of increased TNF-α in AD. TNFR1 protein levels in human post-mortem AD brain tissue are significantly increased as compared to non-demented age-matched controls, while TNFR2 protein levels are decreased [88,93]. Moreover, it appeared that TNF-α in the AD brain has an increased binding affinity to TNFR1 but a decreased affinity for TNFR2 [94]. Interestingly, Zhao et al. also reported significantly increased levels of TRADD and caspase-3 in AD brains [88]. Data from these studies suggest a shift towards TNFR1-mediated signaling in AD. On a genetic level, a polymorphism in exon 6 of the TNFR2 gene is associated with late-onset AD [95]. The functional consequences of this polymorphism in TNFR2, however, remain, to our knowledge, unclear.
Studies using AD mouse models also have aimed to further the understanding of the role of TNF-α receptors in AD pathology. Montgomery et al. (2011) found that deletion of both TNFR1 and TNFR2 in triple-transgenic AD mice (3xTg-AD) significantly exacerbated AD pathology [96]. This suggests that total blockage of TNF-α signaling is not beneficial in this condition, and that both TNFRs should be appreciated separately. Interestingly, Montgomery et al. (2013) supported this idea by showing that the silencing of TNFR2 aggravates TNFR1-mediated Aβ and tau pathology in aged 3xTg-AD mice [97]. Moreover, knock-down of either TNFR2 or both TNF-α receptors caused enhanced neuroinflammation [97]. Likewise, the group of Shen recently reported that genetic deletion of TNFR2 enhances AD pathology in the APP23 mouse model for AD, while TNFR2 overexpression can reverse these findings [98]. The same group also showed that genetic deletion of TNFR1 resulted in inhibition of Aβ production in APP23 mice, and prevented learning and memory deficits [91]. McAlpine et al. showed that the inactivation of TNFR1 signaling diminished Aβ pathology in 3xTgAD mice, and that administration of inhibitors of sTNF-α (which predominantly activates TNFR1) had similar beneficial effects in 3xTgAD mice [99]. Moreover, intracerebroventricular injection of oligomeric Aβ resulted in cognitive decline in wild-type mice, but did not affect cognition in TNFR1 knockout mice [3]. Finally, in an in vitro study with the SH-SY5Y neuroblastoma cell line, silencing of TNFR2 aggravated the neurotoxic effect of Aβ [100]. These findings overall seem to support the hypothesis that increased TNFR1 signaling and/or decreased TNFR2 signaling may play an important role in AD pathology.

3.2. Parkinson’s Disease

Neuroinflammation—besides the aggregation of alpha-synuclein (α-synuclein) proteins—also plays an important role in PD, by directly or indirectly contributing to the degeneration and death of dopaminergic neurons in the substantia nigra [101,102]. The role of TNF-α and its receptors in PD was also previously reviewed by McCoy and Tansey (2008) [103]. TNF-α levels are significantly increased in the brain and CSF of PD patients [102,104], and increased TNFR1 levels were found in the substantia nigra of PD patients [105]. Evidence for the involvement of TNF-α and its receptors in mechanisms of PD progression is described in studies with different PD animal models and in vitro models (also see Table 1). For example, some models aim to mimic the α-synucleinopathy that is observed in PD by overexpressing wild-type or mutant α-synuclein. In vitro, BV2 cells (a murine microglial cell line) showed elevated TNF-α secretion upon α-synuclein overexpression [106], and primary murine microglia presented a significant increase in TNF-α expression after exposure to mutant α-synuclein [107]. In vivo, overexpression of α-synuclein via recombinant adeno-associated virus (AAV-synuclein) injection into the substantia nigra was also found to increase TNF-α expression [108,109]. Another PD model makes use of 6-hydroxydopamine (6-OHDA), a toxic dopamine analogue which leads to dopaminergic neuron death upon administration. In vitro, it was shown that selective activation of TNFR2 (by TNC-scTNFR2, a TNFR2-specific agonist) rescued cultured neurons from 6-OHDA-induced cell death [110]. In vivo, peripheral and intranigral injection in rats with specific inhibitors of sTNF-α (XPro-1595 and XENP345, respectively) was shown to reduce 6-OHDA-induced death of dopamine neurons [111,112,113,114]. Considering that sTNF-α preferably binds and activates TNFR1 rather than TNFR2, and that TNFR1 is highly expressed by dopamine neurons, it was suggested that the neuroprotective effects of these sTNF-α blockers may have resulted mostly from attenuated signaling via TNFR1 [112,115]. These findings indicate that TNF-α and its receptors exert similar functions in PD as previously described for AD; TNF-α functioning is shifted towards increased TNFR1 signaling, and certain neuroprotective effects induced via TNFR2 signaling are decreased. It should be noted, however, that studies using mice with TNFR1 and/or TNFR2 deletions have led to contradictory findings about their roles in PD pathology, which may be due to differences in the PD models used, as reviewed in [103]. For example, it was shown that mice lacking both TNFR1 and TNFR2 in the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP, a dopaminergic neurotoxin) model for PD were completely protected against the dopaminergic neurotoxicity of MPTP, while mice lacking either TNFR1 or TNFR2 were not protected [116].

3.3. Ischemic Stroke

Ischemic stroke can arise when a blood vessel supplying blood to the brain is obstructed. Sudden loss of blood flow to a brain region causes damage and cell death in the (nutrient- and oxygen-) deprived area. Upon ischemic stroke, different brain cell types in proximity of the ischemic lesion site (including neurons, microglia, and astrocytes) increase their production of TNF-α. This has been shown in human brain tissue as well as in experimental animal models of stroke [117,118,119,120]. As reviewed by Pan and Kastin (2007), TNF-α was shown to have both detrimental and beneficial effects in stroke [121]. Several studies reported that inhibition of TNF-α (e.g., by etanercept, a human TNFR2-IgG Fc fusion protein) reduces infarct size and neuroinflammation [122,123,124,125], while, on the other hand, complete knockout of both TNFRs increases the sensitivity for stroke and aggravates neuronal damage [5]. Moreover, in stroke in vitro and animal models, pre-treatment with TNF-α (which models ischemic preconditioning) mediates neuroprotective effects after ischemia [126,127]. In accordance with the above-discussed disorders, complete abolition of TNF-α signaling, as well as exaggerated TNF-α signaling, are detrimental in ischemic stroke. This may likely depend on the contribution of TNF-α/TNFR1 and TNF-α/TNFR2 signaling (also see Table 1). In addition to TNF-α, its receptors are also upregulated in stroke. In a rat model for stroke by permanent middle cerebral artery occlusion (MCAO), TNFR1 upregulation was apparent after 6 h, while TNFR2 upregulation followed at 24 h [121,128]. Time differences in upregulation of TNFR1 and TNFR2 expression can be explained by studies showing that TNFR1 expression is mainly regulated by post-translational processes, while TNFR2 is believed to be controlled by transcriptional factors such as NF-κB [129,130,131]. Studies investigating the effects of TNFR1- and TNFR2-mediated signaling in ischemia and stroke have resulted in contrasting findings. For example, it was shown by Gary et al. (1998) that the infarct size in mice after MCAO is significantly larger in TNFR1 knockout mice than in wild-type or TNFR2 knockout mice [132]. Lambertsen et al. similarly showed larger infarct sizes in TNFR1 knockout mice compared with wild-type and TNFR2 knockout mice in a focal cerebral ischemia model [133]. Moreover, TNFR1 was implicated in ischemic preconditioning, in which a short ischemic event may result in resistance to severe ischemic injury [134]. It was shown that ischemic preconditioning (induced by a 10 min transient MCAO) caused TNFR1 upregulation in neurons, and that this upregulation in TNFR1 expression in ischemic preconditioning was associated with a smaller infarct size [134]. Taoufik et al. reported that TNFR1 signaling is responsible for upregulating different neuroprotective mediators, i.e., vascular endothelial growth factor, upon an ischemic lesion in the mouse brain [135,136]. In addition, a study investigating mice deficient of TNFR1 and transgenic for human TNFR2 implicated that TNFR2 signaling induced pro-inflammatory responses in the CNS vasculature, resulting in inflammatory ischemia [137]. These findings imply a neuroprotective role for TNFR1, while TNFR2 signaling may have detrimental effects by aggravating neuroinflammatory processes. However, conflicting data is also present. For example, our group previously showed that absence of TNFR1 in mice strongly reduced neurodegeneration after retinal ischemia-reperfusion, while a lack of TNFR2 exacerbated neurodegeneration [16]. This finding indicates that TNFR1 signaling may augment neuronal death and TNFR2 may promote neuroprotection. In accordance, an in vitro study with the SH-SY5Y neuroblastoma cell line showed that silencing of TNFR2 aggravated cell injury upon hypoxic conditions [100]. Moreover, in the immature brain, TNFR1-JNK signaling was responsible for neuroinflammation and neurovascular damage in lipopolysaccharide (LPS)-sensitized hypoxic-ischemia brain injury [138]. The different models of ischemia that were used may, in part, explain these contradictory findings. Furthermore, the duration of the induced ischemia (acute/transient vs. chronic) might potentially affect the pathways, kinetics, and outcomes of TNF signaling. Also, the acuteness of ischemic lesions may explain differences between ischemic stroke and other neurodegenerative disorders like AD and PD, which gradually develop over a longer period of time. In disorders that develop slowly, the expression levels and distribution of TNFRs may gradually change during the pathological process (e.g., resulting in lower TNFR2 expression in AD brains). This might explain how acute insults could result in different effects of TNF-α, as compared to conditions in which lesions arise over a longer period of time.

3.4. Multiple Sclerosis

MS is a chronic demyelinating disease of the CNS, resulting in disrupted nerve signaling and therefore a wide range of neurological symptoms. It has been suggested that the demyelination of axons is due to the death of myelin-forming oligodendrocytes, which in part may be caused by detrimental inflammatory and immune responses targeted to these cells [139]. The involvement of TNF-α in MS has been explored in several studies [103] (also see Table 1). Increased TNF-α levels were found in MS lesions [140,141]. In a transgenic mouse model that overexpresses murine TNF-α specifically in the CNS, it was demonstrated that constitutive TNF-α expression leads to spontaneous development of a chronic inflammatory demyelinating disorder [142]. In addition, peripherally increased TNF-α levels have been associated with synaptic instability in the brain, and as such may contribute to sensory and cognitive impairments as seen in MS [143]. On the other hand, complete knockout of TNF-α in experimental autoimmune encephalomyelitis (EAE, an MS animal model) mice caused deleterious effects, including increased inflammation, demyelination, and higher mortality as compared to control mice [144,145]. In the cuprizone model (a toxin causing reversible demyelination), complete knockout of TNF-α in mice resulted in delayed demyelination (suggesting that TNF-α promotes acute demyelination) as well as delayed remyelination (suggesting that in later stages, TNF-α promotes remyelination) [146]. The beneficial versus detrimental effects of TNF-α in MS may greatly depend on its signaling via either TNFR1 or TNFR2. Akassoglou et al. (1998) demonstrated a dominant role for TNFR1 signaling in TNF-mediated oligodendrocyte apoptosis and primary demyelination [147]. In addition, TNFR1 was suggested to contribute to inflammatory infiltration of the EAE spinal cord [148]. Interestingly, it was recently shown in different studies that administration of an antagonistic antibody that selectively targets TNFR1 ameliorated disease symptoms in the EAE mouse model [18,149]. Also, inhibition of sTNF-α by XPro-1595 protected EAE mice from clinical symptoms and improved axon preservation and remyelination, indicating a detrimental effect of sTNF-α (which signals mostly via TNFR1) [150,151]. Furthermore, studies showed that TNFR1 knockout mice do not develop EAE, or have a less severe disease course. TNFR2 knockout mice, on the other hand, were seen to develop more extensive demyelination and aggravated EAE disease symptoms [18,152,153,154]. Similarly, in the cuprizone model, TNFR2 was shown to be responsible for TNF-α mediated remyelination and proliferation of oligodendrocyte precursor cells [146]. A neuroprotective role of TNFR2 on oligodendrocyte progenitor cells was also directly shown in in vitro studies by Maier et al. (2013) [155]. In this study, primary oligodendrocytes from transgenic mice expressing human TNFR2 were shown to be protected from oxidative stress after preconditioning the cells with a TNFR2 specific agonist. This protective effect might be elicited by TNFR2-mediated induction of anti-apoptotic and cell survival genes [155]. Taking the above results together, it may not be a surprise that general blockage of TNF-α signaling can have a net detrimental effect, by also inhibiting the neuroprotective signaling of TNF-α. This idea is supported by different studies, including a phase II study in which administration of the TNF-α antagonist lenercept was associated with exacerbation of symptoms in MS patients [156], and case reports linking etanercept treatment with the onset of MS [157,158]. In general, specifically blocking TNFR1 or stimulating TNFR2 signaling may provide a promising therapeutic possibility in MS. It should be noted, however, that TNFR1 might also have beneficial effects in MS. For example, it has been suggested that TNFR1 signaling is important for the onset of EAE, but also for limiting EAE progression at a later stage [115]. Therefore, specific modulation of TNF-α receptor-mediated signaling at specific stages of the disease may be a promising approach for effective outcomes in MS.
Table 1. Summary of the TNF-α family members that are subjects of this review, and their roles in neurodegenerative conditions.
Table 1. Summary of the TNF-α family members that are subjects of this review, and their roles in neurodegenerative conditions.
ConditionTNF-α family memberTissueFinding ModelRef.
Alzheimer’s disease (AD)TNF-αCNSTNF-α protein levels are increased in AD brain tissue.Human AD patients.[86,87,88]
Plasma and serumTNF-α protein levels are increased in AD plasma and serum.Human AD patients.[83,84,85]
TNFR1 and TNFR2 CNS TNFR1 protein levels are increased, TNFR2 protein levels are decreased.Human AD patients.[88,93]
Deletion of both TNFRs exacerbates AD pathology. 3xTg-AD mouse model.[96]
Silencing or deletion of TNFR2 aggravates AD pathology. TNFR2 overexpression reverses these effects. 3xTg-AD mouse model and APP23 mouse model. [97]
In vitro, TNFR2 silencing promotes Aβ neurotoxic effects. SH-SY5Y cell line. [100]
Deletion of TNFR1 diminishes AD pathology. 3xTg-AD mouse model and APP23 mouse model.[91]
sTNF-α inhibitors diminish AD pathology. 3xTg-AD mouse model.[99]
sTNFR1 and sTNFR2CSF, serum and plasmasTNFR1 levels are increased.
sTNFR2 levels are unchanged or decreased.
Human control and MCI patients.[159,160,161,162,163]
Higher sTNFR1 serum levels can predict conversion from MCI to AD.Human control and MCI patients.[161]
sTNFR1 and sTNFR2 levels correlate with BACE1 activity and Aβ40 levels, as well as with tau CSF levels.Human control and MCI patients.[164]
Parkinson’s disease (PD) TNF-αCNS and CSFTNF-α levels are increased in brain and CSF. Human control and PD patients.[96,98]
TNF-α levels are increased in brain.α-Synuclein overexpression cell line and mouse models. [106]
TNFR1 CNS TNFR1 levels are increased in the substantia nigra. Human control and PD patients.[105]
sTNF-α inhibitors reduce cell death of dopamine neurons.Rat 6-OHDA toxicity model. [111,112,113,114]
TNFR2CNSSelective activation of TNFR2 protects dopaminergic neurons.Neuronal culture, 6-OHDA toxicity model. [110]
TNFR1 and TNFR2CNSDeletion of both TNFRs protects from dopaminergic toxicity, while lack of either TNFRs alone is not protective. Mouse, MPTP toxicity model. [116]
sTNFR1Serum and plasmaSerum sTNFR1 levels are increased. Human control and PD patients.[102,104,165]
Higher serum sTNFR1 correlate with a later onset of sporadic PD.Human control and PD patients.[165]
Elevated plasma sTNFR1 levels predict poorer executive functioning in PD. Human control and PD patients.[166]
Ischemic stroke TNF-α CNS TNF-α production is increased around the lesion site. Human brain tissue and animal models of stroke. [117,118,119,120]
Inhibition of TNF-α reduces infarct size and neuroinflammation. Stroke mouse models. [122,123,124,125]
TNFR1CNSTNFR1 knockout mice have larger infarct sizes compared to wild-type and TNFR2 knockout mice. Stroke mouse model.[134,135]
TNFR1 is responsible for expression of neuroprotective factors upon ischemia. Stroke mouse model.[135,136]
Absence of TNFR1 reduces retinal ischemia-reperfusion damage. Mouse retinal ischemia-reperfusion model. [16]
TNFR1 signaling causes neuroinflammation and neurovascular damage in the immature brain. LPS-sensitized hypoxic-ischemia mouse model. [138]
TNFR2CNSAbsence of TNFR2 aggravates retinal ischemia-reperfusion damage. Mouse retinal ischemia-reperfusion model.[16]
TNFR2 silencing increases cell injury upon hypoxic conditions.SH-SY5Y cell line.[100]
TNFR2 signaling can result in inflammatory ischemia.Stroke mouse model.[137]
TNFR1 and TNFR2CNSDeletion of both TNFRs aggravates neuronal damage. Stroke mouse model. [5]
Multiple sclerosis (MS) TNF-α CNS TNF-α levels are increased in MS lesions.Human MS brain tissue. [140,141]
Constitutive TNF-α overexpression can cause a spontaneous inflammatory demyelinating disorder.TNF-overexpressing mouse model.[142]
TNF-α knockout increases demyelination and inflammation. EAE mouse model. [144,145]
TNF-α knockout delays both demyelination and remyelination. Cuprizone mouse model.[146]
General blockage of TNF-α by etanercept is linked to onset of MS in human case reports.Human case reports. [157,158]
General blockage of TNF-α by lenercept may exacerbate symptoms in human MS patients.Human MS patients. [156]
TNFR1 CNS TNFR1 knockout mice do not develop EAE or have a less severe disease course.EAE mouse model. [18,152,153,154]
TNFR1 signaling induces oligodendrocyte apoptosis and primary demyelination. TNF-transgenic mice. [147]
TNFR1 may contribute to inflammatory infiltration of the spinal cord.EAE mouse model.[148]
Selective inhibition of TNFR1 signaling ameliorates EAE-induced pathology. EAE mouse model. [18,149]
sTNF-α inhibition protects against EAE symptoms. EAE mouse model. [150,151]
TNFR2 CNS TNFR2 knockout mice show aggravated demyelination and disease symptoms. EAE mouse model. [18,152,153,154]
TNFR2 signaling mediates remyelination and oligodendrocyte precursor cell proliferation. Cuprizone mouse model. [146]
Selective stimulation of TNFR2 protects primary oligodendrocytes from oxidative stress. Primary oligodendrocyte cell culture. [155]

3.5. Other Neurodegenerative Disorders

Besides the four conditions described above, there are certainly many other disorders with neurodegenerative features in which a role for TNF-α has become clear. Although for this review we have chosen to focus on AD, PD, ischemic stroke, and MS, investigation of TNF-α and its receptors in other neurodegenerative conditions may also greatly contribute to the understanding of TNF-α’s effects, and the factors on which these effects depend. Examples of other disorders in which TNF-α has been implicated include traumatic brain injury (TBI) [167], epilepsy [168], and Huntington’s disease (HD) [169,170]. Evidence exists that TNFR1 signaling may exacerbate cognitive dysfunction in a mouse model of TBI, while TNFR2 signaling may attenuate it [171,172]. Also, in models of epileptic seizures, inhibition of TNFR1 signaling as well as activation of TNFR2 were suggested to protect against seizure-induced neuronal damage [168,173,174]. In in vitro and in vivo models of HD, blockage of sTNF-α by XPro-1595 was shown to reduce different pathological features of HD [175]. Another group of diseases in which TNF-α signaling may play an important role is lysosomal storage disease (LSD). LSDs are rare, and result from mutations in lysosomal enzyme-encoding genes, causing the enzyme’s substrate to accumulate in the lysosomes. Depending on the enzyme that is affected, different substrates may pile up, leading to different LSDs. More than 30 LSDs are known, and include, for example, Fabry disease, Pompe disease, Gaucher disease, and Niemann-Pick type C (NP-C) disease [176]. In the majority of LSDs neurodegeneration occurs, with neuroinflammatory processes being implicated as important contributors [177,178,179]. In human NP-C patient brain tissue as well as in a mouse model of this disease, apoptotic neurons were detected. Interestingly, in affected brain regions in an NP-C mouse model, the expression of different components in TNF-mediated apoptotic signaling was found to be increased, including that of TNF-α itself, TNFR1, and caspase-8 [180]. Gaucher disease patients showed elevated serum TNF-α levels, and in the fetal brains of a Gaucher disease mouse model, TNF-α levels (as well as the levels of different other pro-inflammatory cytokines) were increased [181,182]. Also, after birth, TNF-α and TNFR1 were found to be upregulated in the brains of Gaucher disease mice with increasing age and disease severity [183]. All in all, there are many conditions with neurodegenerative components in which TNF-α signaling may significantly contribute to neuropathological processes, and more research focusing on TNF-α signaling via either TNFR1 and TNFR2 is warranted.

4. TNFR1- and TNFR2-Mediated Signaling in Neurodegeneration

Despite the overlap between the signaling pathways of TNFR1 and TNFR2, their effects can differ greatly. For example, although both receptors may cause activation of transcription factor NF-κB (however with different activation kinetics [59]), different genes are transcribed depending on which TNFR was activated. The involvement of possible TNFR1 and TNFR2 downstream signaling pathways in neurodegenerative disorders will be discussed based on studies using TNFR1- and/or TNFR2-specific knockout animals, or compounds targeting TNFRs specifically.

4.1. TNFR1—Possible Downstream Targets in Neurodegeneration

Neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin 2, the murine orthologue of NGAL) is a recently described downstream product of TNFR1-mediated signaling [184]. NGAL plays a role in the innate immune system, and is important in the defense against certain bacteria [185]. Mounting evidence recently provided insights into interesting functions of NGAL in the brain, particularly its role in neurodegenerative disorders. Robust increased NGAL protein levels were found in AD post-mortem human brain tissue [184], a mouse model for MS [186], and mouse model for cerebral ischemia [187]. Increased NGAL protein levels are detrimental to neuronal health [188] and sensitize neurons and other brain cell types to cell death upon exposure to Aβ and oxidative stress [184,189,190]. In addition, NGAL was shown to further promote pro-inflammatory reactions, and to stimulate classical inflammatory activation of microglia and astrocytes [191,192]. NGAL plays an interesting role in TNF-α-mediated signaling pathways. Our research group showed that NGAL is solely increased and secreted upon TNFR1 stimulation in murine primary neurons, astrocytes, and microglia cells. Increased NGAL in turn silences the TNFR2-mediated PI3K-PKB/Akt pathway in neurons, possibly by increasing PTEN levels [184]. Thus, NGAL may play an important role in shifting TNF-α signaling towards TNFR1-mediated pathways observed in different neurodegenerative conditions, as previously described in this review.
Different studies demonstrated that TNFR1 can induce matrix metalloproteinase 9 (MMP-9) expression [193,194,195]. In the A549 cell line (a human lung adenocarcinoma epithelial cell line), TNF-α can induce MMP-9 expression via a TNFR1/TRAF2/PKC alpha-dependent pathway [193]. MMP-9 has been associated with different physiological and pathophysiological processes. For example, MMP-9 was shown to be able to interact with Aβ, and can play a role in the disruption of the blood-brain barrier [196,197,198,199]. This latter effect seems to be associated with MMP-9’s actions in the degradation of the extracellular matrix. Of note, it was shown that MMP-9 can form a complex with NGAL, and that NGAL may elongate the activity of MMP-9 [200].
TNFR1 could engage in processes concerning the clustering of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor (AMPAR). Deletion of TNFR1 was found to suppress excitatory synaptic transmission via the localization of AMPA receptors to the synapses of cortical neurons [201]. It was therefore suggested that TNFR1 might be involved in AMPAR-mediated excitotoxicity. Furthermore, it was shown that TNFR1 signaling induces excitotoxicity by promoting glutamate release in mouse primary microglia and astrocyte cell cultures [202,203,204]. More specific to AD, TNFR1 was found to be involved in the processing of the amyloid precursor protein (APP) and Aβ plaque formation by increasing BACE1 promotor activity [91].

4.2. TNFR2—Possible Downstream Targets in Neurodegeneration

Examples of TNFR2-specific signaling in neurodegeneration have also been described [16,59]. Dolga et al. identified certain small conductance calcium-activated potassium K(Ca)2 channels as downstream products of TNFR2 signaling [129,205]. These channels contribute to neuroprotection against neuronal overstimulation by lowering the neuronal excitability. It is specifically the expression of K(Ca)2.2 that was shown to be downstream of TNF-α/TNFR2 signaling via NF-κB activation. As such, it was suggested that in primary cortical neurons, TNF-α induces K(Ca)2.2 channel activation, resulting in neurons that are more resistant to excitotoxic cell death by preventing intracellular calcium levels to become pathologically high [129,205]. In the past years it has been shown that K(Ca)2 channels may also be involved in mechanisms contributing to the plasticity of the hippocampal CA1 neurons and in learning and memory [206,207].
Fischer et al. (2014) showed that TNFR2-mediated activation of the PI3K-PKB/Akt pathway in primary astrocytes induces the expression of different neuroprotective genes, including the gene that encodes leukemia inhibitory factor (LIF) [208]. LIF is a neurotrophic cytokine, which, in the brain, is mainly produced by astrocytes. Elevated levels of LIF were shown to promote the maturation of oligodendrocytes [208], and LIF was found to protect primary neurons against excitotoxicity [209]. Moreover, in the EAE mouse model LIF was demonstrated to protect axons in the brain from acute inflammatory damage [210].
Other downstream products of TNFR2 signaling include CXCL12, which has also been implicated in the proliferation and differentiation of oligodendrocyte progenitor cells [211]. Moreover, its levels were found downregulated in the Tg2576 AD mouse model, and reduced CXCL12 levels were shown to cause impairments in learning and memory [212]. Lastly, TNFR2 signaling in microglia has been related with the induction of anti-inflammatory pathways, for example the upregulation of IL-10 [213].
All examples discussed in this chapter support the idea that TNFR1 may specifically induce factors that contribute to neurodegenerative processes, while TNFR2 specifically mediates factors involved in neuroprotective mechanisms (Figure 3). However, in agreement with the rest of this review, things are certainly far more complex. Therefore, different unknowns and contradictory findings underlining and adding to the complexity of TNF signaling will be addressed in the following chapter.
Figure 3. Examples of specific downstream targets of TNFR1 and TNFR2 that may be involved in neurodegenerative disorders. Dotted lines indicate existing potential therapeutic approaches. Other general TNF-α blockers, not depicted in this figure, include adalimumab, certolizumab pegol, and golimumab. Other new TNFR1-specific antagonists include DMS5540 and TROS (also see review by Fischer et al., 2015 [214]).
Figure 3. Examples of specific downstream targets of TNFR1 and TNFR2 that may be involved in neurodegenerative disorders. Dotted lines indicate existing potential therapeutic approaches. Other general TNF-α blockers, not depicted in this figure, include adalimumab, certolizumab pegol, and golimumab. Other new TNFR1-specific antagonists include DMS5540 and TROS (also see review by Fischer et al., 2015 [214]).
Antibodies 04 00369 g003

5. Complex matters: TNFR1 Signaling Is Primarily Damaging and TNFR2 Beneficial?

Although in this paper we generally highlighted an important neuroprotective role for TNFR2 and a neurodegenerative role for TNFR1 in different neurodegenerative disorders, findings that contradict this idea cannot be ignored. As described in the previous paragraphs, for several neurodegenerative disorders conflicting results have been found concerning beneficial/detrimental effects of TNFR1 and TNFR2 signaling. These contradictory findings emphasize the complexity of TNFR1/TNFR2 signaling, and confirm that our understanding of TNF signaling is still a work in progress.
The outcome of TNF-α signaling will likely depend on many variables: the availability of both receptors, the available levels of sTNF-α and mTNF-α ligands, the availability of the components in their respective signaling cascades, and the level of crosstalk between the two pathways, all of which likely depend on the cell type, tissue, and the condition. Indeed, different studies have suggested that TNF-α signaling may be strongly brain region-specific, which may in part depend on, e.g., the relative density and activity of microglia in specific regions [213,215,216]. Also, the timing of TNF-α signaling in different stages of neurodegeneration could affect the outcomes of TNF-α. For example, TNF-α mediates a neuroprotective effect when hippocampal organotypic slice cultures are treated with TNF-α before an ischemic insult (which may simulate ischemic preconditioning), but has neurotoxic effects when administered after the same ischemic insult [217]. Furthermore, TNFR2-mediated pathways have received less attention compared to TNFR1, and undefined signaling mechanisms possibly remain to be discovered. These and other factors greatly increase the complexity of TNF signaling, and a few will be further discussed below.

5.1. Selective Harmful Downstream Targets of TNFR1 and Beneficial Downstream Targets of TNFR2?

Although Chapter 4 described examples supporting the presence of potent detrimental downstream signaling pathways mediated specifically via TNFR1, while TNFR2 signaling may mostly activate genes with potential neuroprotective functions, matters are often not that clear-cut. For instance, it should be noted that there are certain examples available of neuroprotective pathways induced via TNFR1, and damaging outcomes of TNFR2 signaling. For example, a known downstream target of TNFR1 is nerve growth factor (NGF), which is important for the survival and growth of neurons [218], while TNFR2 may also promote expression of potentially detrimental factors, such as intercellular adhesion molecule-1 (ICAM-1), which has been associated with neuroinflammation and neurodegeneration [219,220]. Moreover, the specificity of certain downstream products to either TNFR1 or TNFR2 is sometimes unclear. For example, some studies have implied NGF to be solely induced via TNFR1 in fibroblasts, while it appeared in astrocytes that signaling via both receptors can cause NGF production [218,221]. Such contradictory findings may, among others, depend on variables like the cell type studied, the proximate cellular conditions, TNFR1-TNFR2 signaling kinetics, and crosstalk between the receptors. In addition, although the above-described processes were found to be specifically induced via either TNFR1 or TNFR2, there may very well be multiple other (TNF-α-independent) pathways that may influence TNF-α-mediated pathways and their outcomes. For example, it may be good to keep in mind that lymphotoxin α (TNF-β) can also bind both TNFR1 and TNFR2. Comparable to TNF-α, lymphotoxin α also has been implicated in different processes in the brain, and in the pathogenesis of conditions including MS [222,223].

5.2. Soluble TNF Receptors

Adding to the complexity of TNF-α signaling, besides membrane TNF receptors (mTNFRs), soluble TNF receptors (sTNFRs) also exist, which influence TNF-α signaling mechanisms as well. sTNFRs (sTNFR1 and sTNFR2) can be formed via a process known as ectodomain shedding, in which the extracellular domains of membrane TNFRs are cleaved off by TACE (which thus shows to have more targets besides mTNF-α) and released into the extracellular space. Notably, in addition to ectodomain shedding, it has been described that TNFR1 can also end up in the extracellular space via exocytosis. This generates exosome-like vesicles with full-length TNFR1 incorporated in the vesicle membrane [224]. The exact functions and mechanisms of actions of sTNFRs (as well as the full-length TNFR1 within vesicles), however, remain elusive. Shedding of mTNFRs is thought to regulate the actions of TNF-α, firstly by diminishing the number of mTNFRs on the cell membrane, and secondly by binding of sTNFRs to TNF-α, thereby preventing TNF-α from binding to and activating mTNFRs. Alternatively, it was suggested that sTNFRs bind to sTNF-α and subsequently stabilize and preserve the bio-active trimeric forms of TNF-α [225]. As such, sTNFRs levels might reflect the activity of TNF-α. Interestingly, intravenous injection of TNF-α in human volunteers suggested that TNF-α is a potent mediator of increased sTNFR1 and sTNFR2 release [226].
Different studies indicate that the levels of sTNFR1 as well as TACE activity are increased in plasma, serum, and CSF from AD patients [159,160,161,162,163]. Moreover, Diniz et al. (2010) showed that higher serum sTNFR1 levels can predict conversion from mild cognitive impairment (MCI) to AD [161]. Plasma and CSF sTNFR2 levels were found to be increased in AD by some groups [159,160], while other studies showed no differences in sTNFR2 levels [161,162]. Similar to AD, increased serum sTNFR1 levels were found in patients with PD [102,104,165]. Also, a single nucleotide polymorphism in the gene encoding TNFR1, resulting in production of a soluble form of TNFR1 that is able to antagonize TNF-α, was found to be associated with MS [227]. Although in these cases the exact meaning of these increased serum sTNFR1 levels is not clear, it was found that higher serum sTNFR1 levels are associated with a later onset of sporadic PD [165]. In addition to the potential functions and effects of sTNFRs described above, sTNFRs may also influence TNF-α signaling via reverse signaling through mTNF-α.
Besides being a ligand for TNFR1 and TNFR2, mTNF-α can also act as a receptor itself. Thus, in addition to inducing a signaling cascade in TNFR1/TNFR2-expressing cells, mTNF-α can also elicit a signal transduction pathway back into the cell on which it is expressed [228]. This process is called reverse signaling, and can occur when mTNF-α is bound by a (s)TNFR or agonistic antibody [228,229]. sTNFRs may have significant effects on cells by inducing reverse signaling. For example, it was reported that sTNFR1 can induce apoptosis of monocytes through reverse signaling via mTNF-α. It appeared that this sTNFR1-induced apoptosis is independent of death receptor pathways, but is mediated via autocrine transforming growth factor beta (TGF-β) through p38 MAPK [230]. In addition, it was recently shown in cultured superior cervical ganglion (SCG) neurons that sTNFR1 promotes sympathetic axon growth and branching through reverse signaling via mTNF-α, and relies on downstream activation of ERK [231].
In addition to endogenous (s)TNFRs, different TNF-α inhibitors (such as etanercept and infliximab) can induce reverse signaling through mTNF-α as well. As suggested in recent studies, effects of such compounds may significantly depend on reverse signaling, besides the effects arising from the prevention of mTNF-α and sTNF-α to bind their TNFRs [232,233].
Taken together, soluble TNFRs may play a substantial role in how TNF-α interacts and functions with its receptors, possibly especially in a systemic pro-inflammatory environment. This is an interesting and noteworthy research field that can provide important insights in TNF-α functioning. In theory, a potential therapeutic strategy to reduce excessive TNFR1 signaling may be to stimulate TNFR1 ectodomain shedding. Interestingly, some mediators (with aminopeptidase regulator of TNFR1 shedding (ARTS-1) appearing as a key regulator) have been identified that are essential for TNFR1 shedding but do not affect TNFR2 shedding [234,235]. While ARTS-1 also participates in shedding of other receptors besides TNFR1 (including IL-6R and IL-1R2 [236]), downstream effectors of ARTS-1 may prove to be TNFR1-specific, and could provide a therapeutic target.

5.3. Interaction between TNFR2 and Interleukin-17 Receptor D

Moreover, the signaling of membrane TNFRs may also hold more complexity than has become clear so far. For example, it was very recently demonstrated that TNFR2 (but not TNFR1) can form a heteromer with interleukin-17 receptor D (IL-17RD, also known as Sef), leading to activation of NF-κB signaling via TRAF2 recruitment [237]. Depletion of IL-17RD was found to impair TNFR2-mediated activation of NF-κB. The complex between IL-17RD and TNFR2 was shown to be formed in HK-2 and 786-O cell lines (a human proximal tubular cell line derived from normal kidney and a human renal cell adenocarcinoma cell line, respectively), and also in rat and mouse renal tissue. This indicates that the interaction between TNFR2 and IL-17RD may arise under physiological conditions [237].
All these complex issues and unknowns emphasize that gaps remain in the basic understanding of TNF-α signaling, which may challenge the identification of suitable TNF-targeting therapeutics for different neurodegenerative disorders.

6. Targeting TNF-α Signaling: An Opportunity for Treatment of Neurodegenerative Disorders?

As concluded in this review, targeting TNF-α signaling towards its neuroprotective functioning could provide potent therapeutic strategies for patients with neurodegenerative disorders. It seems that therapeutics could aim at a certain step of TNF-α-mediated signaling pathways via inhibiting detrimental pathways.

6.1. Targeting TNF-α as Treatment for Neurodegenerative Disorders

Because TNF-α is a key inductor in some inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), Crohn’s disease (CD), as well as some neurodegenerative disorders, directly inhibiting this cytokine could prevent or treat those conditions. A number of researchers have demonstrated that directly blocking the actions of TNF-α via anti-TNF-α antibodies and its antagonists indeed can ameliorate inflammatory and neurodegenerative disorders [238,239,240]. Additionally, inhibition of sTNF-α was shown to promote axon preservation and remyelination in the EAE mouse model [151]. Due to its therapeutic capability, treatments aimed at inhibiting the functions of TNF-α have been shown as effective treatment strategies for RA, PsA, and CD in experimental trials and are currently being used worldwide in the clinical setting [19,241,242,243]. So far, pharmaceutical anti-TNF-α agents that include thalidomide analogues which inhibit the production of TNF-α have been applied for the treatment of RA [244,245,246]. Moreover, other pharmaceutical agents including etanercept, adalimumab, and infliximab, which can bind both sTNF-α and mTNF-α, thereby inhibiting their signaling, have been successfully applied for treatment for RA and PsA [247]. Studies into the effects of such pharmaceuticals in neurodegenerative disorders like AD, PD, and MS, however, remain limited.
Drugs targeting TNF-α for systemic inflammatory diseases still have adverse effects in a minority of patients [248]. For instance, anti-TNF-α therapy for RA induces the risk of serious infections of the skin, soft tissues, and joints [249]. Anti-TNF-α agents increase risk rates of malignancies in patients with inflammatory bowel disease [250]. It has been mentioned that two patients with rheumatoid arthritis treated with an anti-TNF-α strategy developed neurological symptoms, including demyelination lesions [251]. Furthermore, it was shown that newborns presented severe neutropenia after their mothers were treated with infliximab for ulcerative colitis during pregnancy [252].
To reduce or diminish the drawbacks of anti-TNF-α agents in inflammatory diseases and neurodegenerative disorders, other therapeutic strategies should be investigated. Considering the various outcomes of TNF-α, targeting a specific point in its signaling pathways could be more effective and decrease the negative effects associated with anti-TNF-α agents.

6.2. Targeting TNFRs as Treatment for Neurodegenerative Disorders

In essence, TNFR1 has often been demonstrated to deteriorate or aggravate neurodegeneration, whereas TNFR2 mediates neuroprotection. Therapeutics that specifically modulate the signaling mechanisms of TNF-α, i.e., blocking TNFR1 actions and/or increasing the TNFR2 signaling pathway, could greatly reduce the side effects of current anti-TNF-α approaches. Sedger’s group [253] discovered that a leporipoxvirus TNF receptor homolog by its N-terminal preligand assembly domain (PLAD)-homologous domain interacts with the intracellular domain of TNFR1 and showed that this interaction results in a heterocomplex that inhibits TNFR1 downstream signaling and significantly prevents TNFR1-induced apoptosis of lymphocytes. Selectively blocking the bioactivity of sTNF-α, thus preventing TNFR1-mediated signaling, attenuated the pathological symptoms in EAE mice [150,151]. Furthermore, a soluble TNFR1-selective antagonistic mutant TNF (named R1antTNF) ameliorated the symptoms in EAE mice [149,254]. Currently, an antagonistic TNFR1-specific antibody has been produced and demonstrated to treat MS clinical symptoms more efficiently in EAE mouse model [18]. Another human TNFR1-specific antagonistic antibody that may prove to have therapeutic effects is ATROSAB [255,256].
As TNFR1 is mainly activated by sTNF-α, selectively inhibiting sTNF-α may prevent TNFR1-mediated apoptosis and could be a therapeutic strategy in neurodegenerative disorders. In this regard, a blocker of sTNF-α, XPro-1595, significantly improved the cognitive deficits induced by spinal cord injury in mice compared to the drug etanercept [257]. Furthermore, Tansey et al. [258] discovered that XPro-1595 significantly reduced activation of microglia and astrocytes, and prevented loss of dopamine neurons in a rat model of PD. Shedding of TNFR1 mediated by iNOS-cGMP-TACE signaling has been suggested to significantly ameliorate the inflammation associated with sepsis [259]. Increased sTNFR1 levels resulting from this TNFR1 shedding could compete to bind to sTNF-α and impair TNFR1-mediated downstream signaling pathways and potentially reduce its apoptotic signaling pathways.
TNFR2-mediated signaling could be used as a therapeutic approach for neurodegenerative disorders. Lovastatin, which is widely used to reduce cholesterol levels in patients, has been confirmed to selectively increase TNFR2 expression [260]. Thereafter, it was demonstrated that lovastatin protected primary cortical neurons against glutamate-induced excitotoxicity [261]. Moreover, in vivo evidence showed that lovastatin attenuated NMDA-induced nucleus basalis magnocelullaris (NBM) lesions and prevented cognitive deficits in mice [262]. This further supports the idea that TNFR2 activation could be a therapeutic approach for neurodegenerative disorders. Notably, Pfizenmaier’s group [110] constructed a soluble human TNFR2-selective agonist (TNC-scTNFR2) and demonstrated that it successfully rescues human neurons from oxidative stress-induced cell death. TNC-scTNFR2 is synthesized by genetic fusion of the trimerization domain of tenascin C to a TNFR2-selective single-chain TNF molecule, which specifically activates TNFR2 to promote the PI3K-PKB/Akt-NF-κB signaling pathway and promotes neuroprotection.
Selective targeting of TNFRs as a therapeutic strategy seems a promising avenue for the treatment of CNS conditions and some inflammatory diseases associated with TNF-α. Of note, it should be established whether simultaneous targeting of both receptors is necessary to achieve maximum therapeutic efficacy, as compared to inhibition/stimulation of either TNFR1 or TNFR2. Moreover, the ability of therapeutic compounds to cross the blood-brain barrier (BBB) is an obstacle that needs urgent attention. TNF-α blockers like etanercept and infliximab are too large to penetrate the BBB and, of certain new compounds, it is yet to be examined whether they can pass the BBB. In the EAE mouse model, subcutaneous or intraperitoneal injections with XPro-1595 and R1antTNF were effective in reducing pathology [149,150,151]. However, seeing the involvement of the peripheral immune system in MS and EAE, it may be that targeting peripheral TNF-α is sufficient to reach therapeutic effects. Moreover, since the BBB is compromised in the EAE model, a possibility exists that these compounds may have entered the brain through an already leaky BBB. Nevertheless, a recent study on XPro-1595 in the 6-OHDA model for PD (in which the BBB is presumably not damaged enough to let XPro-1595 pass non-selectively) revealed that this compound could indeed reach the brain in therapeutically relevant concentrations (evidenced by inhibited glial activation and reduced dopamine neuron loss), after subcutaneous administration [258]. Moreover, it may be that certain compounds, in certain conditions, do not necessarily have to pass the BBB to reach therapeutic effects. For example, in rat MCAO models for cerebral ischemia beneficial effects were reported upon intraperitoneal injection of etanercept [124,125]. However, it may be that etanercept could enter the brain via disruptions in the BBB, induced by the MCAO [124]. Other important issues that will need to be addressed include the timing of treatment, and the potential side-effects that may arise from targeting TNF-α, TNFR1, and/or TNFR2. In case of ischemic stroke, start the treatment within a few hours upon an insult may be crucial to limit damage as much as possible. As described in Chapter 3.3, the timing of specific TNF treatments may be particularly delicate in acute conditions where TNFR expression levels may be rather dynamic in the first hours/days, for example after the stroke. Apoptotic signaling may be beneficial immediately upon an insult in order to clear damaged cells and protect surrounding cells. As such, administering, e.g., TNFR1 antagonists, may have to be very carefully timed, neither too early nor too late. However, for chronic conditions such as AD, PD, and MS, it can be hypothesized that beginning treatment in early stages may in the end prove to be most effective, but starting treatment in later stages may well slow down the neurodegenerative process. Furthermore, potential side-effects of TNF-targeting compounds have to be assessed. For example, the possibility that selective inhibition of TNFR1 or stimulation of TNFR2 signaling could negatively affect production or action of neurotrophic factors (such as NGF and BDNF) should be explored in future studies.

7. Conclusions

As discussed in this review, TNF-α is involved in many neurodegenerative disorders by exerting both neuroprotective and neurodegenerative functions. A balance between these opposite effects seems to depend on its actions via TNFR1 and TNFR2. A thorough understanding of TNF-α signaling pathways can contribute to the development of potential therapeutic strategies. Focusing on multiple molecular interactions, which can control signaling outcomes in TNF-α signaling pathways, could be critical to develop preferable therapeutic strategies in the future.


ULME and PPDD are supported by Internationale Stichting Alzheimer Onderzoek, and PJWN, PPDD and ULME are funded by ZonMW Deltaplan Dementie Memorabel. PPDD is supported by a research grant of the Interuniversity Poles of Attraction (IAP Network P7/16) of the Belgian Federal Science Policy Office. DWD is supported by a grant of the Research School of Behavioral and Cognitive Neurosciences.

Author Contributions

Yun Dong and Doortje W. Dekens wrote the manuscript and designed the figures. Peter Paul De Deyn, Petrus J.W. Naudé and Ulrich L. M. Eisel reviewed and revised the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Moriwaki, K.; Bertin, J.; Gough, P.J.; Orlowski, G.M.; Chan, F.K.M. Differential roles of RIPK1 and RIPK3 in TNF-induced necroptosis and chemotherapeutic agent-induced cell death. Cell Death Dis. 2015, 6, e1636. [Google Scholar] [CrossRef] [PubMed]
  2. Siebert, S.; Tsoukas, A.; Robertson, J.; McInnes, I. Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol. Rev. 2015, 67, 280–309. [Google Scholar] [CrossRef] [PubMed]
  3. Lourenco, M.V.; Clarke, J.R.; Frozza, R.L.; Bomfim, T.R.; Forny-Germano, L.; Batista, A.F.; Sathler, L.B.; Brito-Moreira, J.; Amaral, O.B.; Silva, C.A.; et al. TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s β-amyloid oligomers in mice and monkeys. Cell Metab. 2013, 18, 831–843. [Google Scholar] [CrossRef] [PubMed]
  4. Franciotta, D.M.; Grimaldi, L.M.; Martino, G.V.; Piccolo, G.; Bergamaschi, R.; Citterio, A.; Melzi d’Eril, G.V. Tumor necrosis factor in serum and cerebrospinal fluid of patients with multiple sclerosis. Ann. Neurol. 1989, 26, 787–789. [Google Scholar] [CrossRef] [PubMed]
  5. Bruce, A.J.; Boling, W.; Kindy, M.S.; Peschon, J.; Kraemer, P.J.; Carpenter, M.K.; Holtsberg, F.W.; Mattson, M.P. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat. Med. 1996, 2, 788–794. [Google Scholar] [CrossRef] [PubMed]
  6. Loetscher, H.; Pan, Y.C.; Lahm, H.W.; Gentz, R.; Brockhaus, M.; Tabuchi, H.; Lesslauer, W. Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell 1990, 61, 351–359. [Google Scholar] [CrossRef]
  7. Schall, T.J.; Lewis, M.; Koller, K.J.; Lee, A.; Rice, G.C.; Wong, G.H.; Gatanaga, T.; Granger, G.A.; Lentz, R.; Raab, H. Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell 1990, 61, 361–370. [Google Scholar] [CrossRef]
  8. Smith, C.A.; Davis, T.; Anderson, D.; Solam, L.; Beckmann, M.P.; Jerzy, R.; Dower, S.K.; Cosman, D.; Goodwin, R.G. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 1990, 248, 1019–1023. [Google Scholar] [CrossRef] [PubMed]
  9. Cabal-Hierro, L.; Lazo, P.S. Signal transduction by tumor necrosis factor receptors. Cell. Signal. 2012, 24, 1297–1305. [Google Scholar] [CrossRef] [PubMed]
  10. Grell, M.; Douni, E.; Wajant, H.; Löhden, M.; Clauss, M.; Maxeiner, B.; Georgopoulos, S.; Lesslauer, W.; Kollias, G.; Pfizenmaier, K.; et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 1995, 83, 793–802. [Google Scholar] [CrossRef]
  11. Fiers, W.; Beyaert, R.; Boone, E.; Cornelis, S.; Declercq, W.; Decoster, E.; Denecker, G.; Depuydt, B.; De Valck, D.; De Wilde, G.; et al. TNF-induced intracellular signaling leading to gene induction or to cytotoxicity by necrosis or by apoptosis. J. Inflamm. 1995, 47, 67–75. [Google Scholar] [PubMed]
  12. Weiss, T.; Grell, M.; Hessabi, B.; Bourteele, S.; Müller, G.; Scheurich, P.; Wajant, H. Enhancement of TNF receptor p60-mediated cytotoxicity by TNF receptor p80: Requirement of the TNF receptor-associated factor-2 binding site. J. Immunol. 1997, 158, 2398–2404. [Google Scholar] [PubMed]
  13. Weiss, T.; Grell, M.; Siemienski, K.; Mühlenbeck, F.; Dürkop, H.; Pfizenmaier, K.; Scheurich, P.; Wajant, H. TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60. J. Immunol. 1998, 161, 3136–3142. [Google Scholar] [PubMed]
  14. Van Herreweghe, F.; Festjens, N.; Declercq, W.; Vandenabeele, P. Tumor necrosis factor-mediated cell death: To break or to burst, that’s the question. Cell. Mol. Life Sci. 2010, 67, 1567–1579. [Google Scholar] [CrossRef] [PubMed]
  15. Okamoto, H.; Kimura, M.; Watanabe, N.; Ogihara, M. Tumor necrosis factor (TNF) receptor-2-mediated DNA synthesis and proliferation in primary cultures of adult rat hepatocytes: The involvement of endogenous transforming growth factor-alpha. Eur. J. Pharmacol. 2009, 604, 12–19. [Google Scholar] [CrossRef] [PubMed]
  16. Fontaine, V.; Mohand-Said, S.; Hanoteau, N.; Fuchs, C.; Pfizenmaier, K.; Eisel, U. Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: Opposite roles of TNF receptor 1 and TNF receptor 2. J. Neurosci. 2002, 22, RC216. [Google Scholar] [PubMed]
  17. Rossi, S.; Motta, C.; Studer, V.; Barbieri, F.; Buttari, F.; Bergami, A.; Sancesario, G.; Bernardini, S.; De Angelis, G.; Martino, G.; et al. Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration. Mult. Scler. 2014, 20, 304–312. [Google Scholar] [CrossRef] [PubMed]
  18. Williams, S.K.; Maier, O.; Fischer, R.; Fairless, R.; Hochmeister, S.; Stojic, A.; Pick, L.; Haar, D.; Musiol, S.; Storch, M.K.; et al. Antibody-mediated inhibition of TNFR1 attenuates disease in a mouse model of multiple sclerosis. PLoS ONE 2014, 9, e90117. [Google Scholar] [CrossRef] [PubMed]
  19. Locksley, R.M.; Killeen, N.; Lenardo, M.J. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 2001, 104, 487–501. [Google Scholar] [CrossRef]
  20. Chan, F.K.; Chun, H.J.; Zheng, L.; Siegel, R.M.; Bui, K.L.; Lenardo, M.J. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 2000, 288, 2351–2354. [Google Scholar] [CrossRef] [PubMed]
  21. Lewis, M.; Tartaglia, L.A.; Lee, A.; Bennett, G.L.; Rice, G.C.; Wong, G.H.; Chen, E.Y.; Goeddel, D.V. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc. Natl. Acad. Sci. USA 1991, 88, 2830–2834. [Google Scholar] [CrossRef] [PubMed]
  22. Tartaglia, L.A.; Ayres, T.M.; Wong, G.H.; Goeddel, D.V. A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993, 74, 845–853. [Google Scholar] [CrossRef]
  23. Chan, F.K.; Chun, H.J.; Zheng, L.; Siegel, R.M.; Bui, K.L.; Lenardo, M.J. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 2000, 288, 2351–2354. [Google Scholar] [CrossRef] [PubMed]
  24. Micheau, O.; Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003, 114, 181–190. [Google Scholar] [CrossRef]
  25. Hsu, H.; Xiong, J.; Goeddel, D.V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995, 81, 495–504. [Google Scholar] [CrossRef]
  26. Chen, N.-J.; Chio, I.I.C.; Lin, W.-J.; Duncan, G.; Chau, H.; Katz, D.; Huang, H.-L.; Pike, K.A.; Hao, Z.; Su, Y.-W.; et al. Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors. Proc. Natl. Acad. Sci. USA 2008, 105, 12429–12434. [Google Scholar] [CrossRef] [PubMed]
  27. Chen, G.; Goeddel, D.V. TNF-R1 signaling: A beautiful pathway. Science 2002, 296, 1634–1635. [Google Scholar] [CrossRef] [PubMed]
  28. O’Donnell, M.A.; Legarda-Addison, D.; Skountzos, P.; Yeh, W.C.; Ting, A.T. Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr. Biol. 2007, 17, 418–424. [Google Scholar] [CrossRef] [PubMed]
  29. Meylan, E.; Burns, K.; Hofmann, K.; Blancheteau, V.; Martinon, F.; Kelliher, M.; Tschopp, J. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat. Immunol. 2004, 5, 503–507. [Google Scholar] [CrossRef] [PubMed]
  30. Wang, C.Y.; Mayo, M.W.; Korneluk, R.G.; Goeddel, D.V.; Baldwin, A.S. NF-kappaB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998, 281, 1680–1683. [Google Scholar] [CrossRef] [PubMed]
  31. Varfolomeev, E.; Goncharov, T.; Fedorova, A.V.; Dynek, J.N.; Zobel, K.; Deshayes, K.; Fairbrother, W.J.; Vucic, D. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J. Biol. Chem. 2008, 283, 24295–24299. [Google Scholar] [CrossRef] [PubMed]
  32. Ea, C.-K.; Deng, L.; Xia, Z.-P.; Pineda, G.; Chen, Z.J. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 2006, 22, 245–257. [Google Scholar] [CrossRef] [PubMed]
  33. Karin, M.; Ben-Neriah, Y. Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annu. Rev. Immunol. 2000, 18, 621–663. [Google Scholar] [CrossRef] [PubMed]
  34. Micheau, O.; Lens, S.; Gaide, O.; Alevizopoulos, K.; Tschopp, J. NF-kappaB signals induce the expression of c-FLIP. Mol. Cell. Biol. 2001, 21, 5299–5305. [Google Scholar] [CrossRef] [PubMed]
  35. Jiang, Y.; Woronicz, J.D.; Liu, W.; Goeddel, D.V. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Science 1999, 283, 543–546. [Google Scholar] [CrossRef] [PubMed]
  36. Juo, P.; Kuo, C.J.; Yuan, J.; Blenis, J. Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr. Biol. 1998, 8, 1001–1008. [Google Scholar] [CrossRef]
  37. Yeh, W.C.; de la Pompa, J.L.; McCurrach, M.E.; Shu, H.B.; Elia, A.J.; Shahinian, A.; Ng, M.; Wakeham, A.; Khoo, W.; Mitchell, K.; et al. FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998, 279, 1954–1958. [Google Scholar] [CrossRef] [PubMed]
  38. Micheau, O.; Lens, S.; Gaide, O.; Alevizopoulos, K.; Tschopp, J. NF-kappaB signals induce the expression of c-FLIP. Mol. Cell. Biol. 2001, 21, 5299–5305. [Google Scholar] [CrossRef] [PubMed]
  39. Micheau, O.; Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003, 114, 181–190. [Google Scholar] [CrossRef]
  40. Holler, N.; Zaru, R.; Micheau, O.; Thome, M.; Attinger, A.; Valitutti, S.; Bodmer, J.L.; Schneider, P.; Seed, B.; Tschopp, J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 2000, 1, 489–495. [Google Scholar] [CrossRef] [PubMed]
  41. Vercammen, D.; Brouckaert, G.; Denecker, G.; Van de Craen, M.; Declercq, W.; Fiers, W.; Vandenabeele, P. Dual signaling of the Fas receptor: Initiation of both apoptotic and necrotic cell death pathways. J. Exp. Med. 1998, 188, 919–930. [Google Scholar] [CrossRef] [PubMed]
  42. Degterev, A.; Huang, Z.; Boyce, M.; Li, Y.; Jagtap, P.; Mizushima, N.; Cuny, G.D.; Mitchison, T.J.; Moskowitz, M.A.; Yuan, J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 2005, 1, 112–119. [Google Scholar] [CrossRef] [PubMed]
  43. Lin, Y.; Choksi, S.; Shen, H.-M.; Yang, Q.-F.; Hur, G.M.; Kim, Y.S.; Tran, J.H.; Nedospasov, S.A.; Liu, Z. Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J. Biol. Chem. 2004, 279, 10822–10828. [Google Scholar] [CrossRef] [PubMed]
  44. Degterev, A.; Hitomi, J.; Germscheid, M.; Ch’en, I.L.; Korkina, O.; Teng, X.; Abbott, D.; Cuny, G.D.; Yuan, C.; Wagner, G.; et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 2008, 4, 313–321. [Google Scholar] [CrossRef] [PubMed]
  45. Cho, Y.S.; Challa, S.; Moquin, D.; Genga, R.; Ray, T.D.; Guildford, M.; Chan, F.K.-M. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009, 137, 1112–1123. [Google Scholar] [CrossRef] [PubMed]
  46. Sun, L.; Wang, H.; Wang, Z.; He, S.; Chen, S.; Liao, D.; Wang, L.; Yan, J.; Liu, W.; Lei, X.; et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012, 148, 213–227. [Google Scholar] [CrossRef] [PubMed]
  47. Chen, W.; Wu, J.; Li, L.; Zhang, Z.; Ren, J.; Liang, Y.; Chen, F.; Yang, C.; Zhou, Z.; Su, S.S.; et al. Ppm1b negatively regulates necroptosis through dephosphorylating Rip3. Nat. Cell Biol. 2015, 17, 434–444. [Google Scholar] [CrossRef] [PubMed]
  48. Chan, F.K.-M.; Shisler, J.; Bixby, J.G.; Felices, M.; Zheng, L.; Appel, M.; Orenstein, J.; Moss, B.; Lenardo, M.J. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J. Biol. Chem. 2003, 278, 51613–51621. [Google Scholar] [CrossRef] [PubMed]
  49. Vieira, M.; Fernandes, J.; Carreto, L.; Anuncibay-Soto, B.; Santos, M.; Han, J.; Fernández-López, A.; Duarte, C.B.; Carvalho, A.L.; Santos, A.E. Ischemic insults induce necroptotic cell death in hippocampal neurons through the up-regulation of endogenous RIP3. Neurobiol. Dis. 2014, 68, 26–36. [Google Scholar] [CrossRef] [PubMed]
  50. Liu, S.; Wang, X.; Li, Y.; Xu, L.; Yu, X.; Ge, L.; Li, J.; Zhu, Y.; He, S. Necroptosis mediates TNF-induced toxicity of hippocampal neurons. BioMed Res. Int. 2014, 2014, 290182. [Google Scholar] [CrossRef] [PubMed]
  51. Fricker, M.; Vilalta, A.; Tolkovsky, A.M.; Brown, G.C. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J. Biol. Chem. 2013, 288, 9145–9152. [Google Scholar] [CrossRef] [PubMed]
  52. Ofengeim, D.; Ito, Y.; Najafov, A.; Zhang, Y.; Shan, B.; DeWitt, J.P.; Ye, J.; Zhang, X.; Chang, A.; Vakifahmetoglu-Norberg, H.; et al. Activation of Necroptosis in Multiple Sclerosis. Cell Rep. 2015, 10, 1836–1849. [Google Scholar] [CrossRef] [PubMed]
  53. Re, D.B.; Le Verche, V.; Yu, C.; Amoroso, M.W.; Politi, K.A.; Phani, S.; Ikiz, B.; Hoffmann, L.; Koolen, M.; Nagata, T.; et al. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 2014, 81, 1001–1008. [Google Scholar] [CrossRef] [PubMed]
  54. Rothe, M.; Pan, M.G.; Henzel, W.J.; Ayres, T.M.; Goeddel, D.V. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 1995, 83, 1243–1252. [Google Scholar] [CrossRef]
  55. Cabal-Hierro, L.; Rodríguez, M.; Artime, N.; Iglesias, J.; Ugarte, L.; Prado, M.A.; Lazo, P.S. TRAF-mediated modulation of NF-kB AND JNK Activation by TNFR2. Cell. Signal. 2014, 26, 2658–2666. [Google Scholar] [CrossRef] [PubMed]
  56. Sun, S.-C.; Ley, S.C. New insights into NF-kappaB regulation and function. Trends Immunol. 2008, 29, 469–478. [Google Scholar] [CrossRef] [PubMed]
  57. Rauert, H.; Wicovsky, A.; Müller, N.; Siegmund, D.; Spindler, V.; Waschke, J.; Kneitz, C.; Wajant, H. Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). J. Biol. Chem. 2010, 285, 7394–7404. [Google Scholar] [CrossRef] [PubMed]
  58. Rodríguez, M.; Cabal-Hierro, L.; Carcedo, M.T.; Iglesias, J.M.; Artime, N.; Darnay, B.G.; Lazo, P.S. NF-kappaB signal triggering and termination by tumor necrosis factor receptor 2. J. Biol. Chem. 2011, 286, 22814–22824. [Google Scholar] [CrossRef] [PubMed]
  59. Marchetti, L.; Klein, M.; Schlett, K.; Pfizenmaier, K.; Eisel, U.L.M. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J. Biol. Chem. 2004, 279, 32869–32881. [Google Scholar] [CrossRef] [PubMed]
  60. Gustin, J.A.; Ozes, O.N.; Akca, H.; Pincheira, R.; Mayo, L.D.; Li, Q.; Guzman, J.R.; Korgaonkar, C.K.; Donner, D.B. Cell type-specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kappa B activation. J. Biol. Chem. 2004, 279, 1615–1620. [Google Scholar] [CrossRef] [PubMed]
  61. Eisel, U.L.M.; Biber, K.; Luiten, P.G.M. Life and Death of Nerve Cells: Therapeutic Cytokine Signaling Pathways. Curr. Signal Transduct. Ther. 2006, 1, 133–146. [Google Scholar] [CrossRef]
  62. Matsuzawa, A.; Tseng, P.-H.; Vallabhapurapu, S.; Luo, J.-L.; Zhang, W.; Wang, H.; Vignali, D.A.A.; Gallagher, E.; Karin, M. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 2008, 321, 663–668. [Google Scholar] [CrossRef] [PubMed]
  63. Ruspi, G.; Schmidt, E.M.; McCann, F.; Feldmann, M.; Williams, R.O.; Stoop, A.A.; Dean, J.L.E. TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. Cell. Signal. 2014, 26, 683–690. [Google Scholar] [CrossRef] [PubMed]
  64. Varfolomeev, E.; Goncharov, T.; Fedorova, A.V.; Dynek, J.N.; Zobel, K.; Deshayes, K.; Fairbrother, W.J.; Vucic, D. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J. Biol. Chem. 2008, 283, 24295–24299. [Google Scholar] [CrossRef] [PubMed]
  65. Baud, V.; Liu, Z.G.; Bennett, B.; Suzuki, N.; Xia, Y.; Karin, M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 1999, 13, 1297–1308. [Google Scholar] [CrossRef] [PubMed]
  66. Chen, Y.R.; Tan, T.H. The c-Jun N-terminal kinase pathway and apoptotic signaling (review). Int. J. Oncol. 2000, 16, 651–662. [Google Scholar] [CrossRef] [PubMed]
  67. Dhanasekaran, D.N.; Reddy, E.P. JNK signaling in apoptosis. Oncogene 2008, 27, 6245–6251. [Google Scholar] [CrossRef] [PubMed]
  68. Tabas, I.; Ron, D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol. 2011, 13, 184–190. [Google Scholar] [CrossRef] [PubMed]
  69. Ji, W.; Li, Y.; Wan, T.; Wang, J.; Zhang, H.; Chen, H.; Min, W. Both internalization and AIP1 association are required for tumor necrosis factor receptor 2-mediated JNK signaling. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 2271–2279. [Google Scholar] [CrossRef] [PubMed]
  70. Cannons, J.L.; Choi, Y.; Watts, T.H. Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response. J. Immunol. 2000, 165, 6193–6204. [Google Scholar] [CrossRef] [PubMed]
  71. Aggarwal, B.B. Signalling pathways of the TNF superfamily: A double-edged sword. Nat. Rev. Immunol. 2003, 3, 745–756. [Google Scholar] [CrossRef] [PubMed]
  72. Baud, V.; Karin, M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001, 11, 372–377. [Google Scholar] [CrossRef]
  73. Naudé, P.J.W.; den Boer, J.A.; Luiten, P.G.M.; Eisel, U.L.M. Tumor necrosis factor receptor cross-talk. FEBS J. 2011, 278, 888–898. [Google Scholar] [CrossRef] [PubMed]
  74. Wang, C.Y.; Mayo, M.W.; Korneluk, R.G.; Goeddel, D.V.; Baldwin, A.S. NF-kappaB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998, 281, 1680–1683. [Google Scholar] [CrossRef] [PubMed]
  75. Fotin-Mleczek, M.; Henkler, F.; Samel, D.; Reichwein, M.; Hausser, A.; Parmryd, I.; Scheurich, P.; Schmid, J.A.; Wajant, H. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. J. Cell Sci. 2002, 115, 2757–2770. [Google Scholar] [PubMed]
  76. Li, X.; Yang, Y.; Ashwell, J.D. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 2002, 416, 345–347. [Google Scholar] [CrossRef] [PubMed]
  77. Qiu, C.; Kivipelto, M.; von Strauss, E. Epidemiology of Alzheimer’s disease: Occurrence, determinants, and strategies toward intervention. Dialogues Clin. Neurosci. 2009, 11, 111–128. [Google Scholar] [PubMed]
  78. McAlpine, F.E.; Tansey, M.G. Neuroinflammation and tumor necrosis factor signaling in the pathophysiology of Alzheimer’s disease. J. Inflamm. Res. 2008, 1, 29–39. [Google Scholar] [PubMed]
  79. Di Bona, D.; Candore, G.; Franceschi, C.; Licastro, F.; Colonna-Romano, G.; Cammà, C.; Lio, D.; Caruso, C. Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer’s disease. Brain Res. Rev. 2009, 61, 60–68. [Google Scholar] [CrossRef] [PubMed]
  80. Kang, H.-J.; Kim, J.-M.; Kim, S.-W.; Shin, I.-S.; Park, S.-W.; Kim, Y.-H.; Yoon, J.-S. Associations of cytokine genes with Alzheimer’s disease and depression in an elderly Korean population. J. Neurol. Neurosurg. Psychiatry 2014, 86, 1002–1007. [Google Scholar] [CrossRef] [PubMed]
  81. Lee, Y.H.; Choi, S.J.; Ji, J.D.; Song, G.G. Association between TNF-α promoter -308 A/G polymorphism and Alzheimer’s disease: A meta-analysis. Neurol. Sci. 2015, 36, 825–832. [Google Scholar] [CrossRef] [PubMed]
  82. Wang, T. TNF-alpha G308A Polymorphism and the Susceptibility to Alzheimer’s Disease: An Updated Meta-analysis. Arch. Med. Res. 2015, 46, 24–30.e1. [Google Scholar] [CrossRef] [PubMed]
  83. Alvarez, A.; Cacabelos, R.; Sanpedro, C.; García-Fantini, M.; Aleixandre, M. Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol. Aging 2007, 28, 533–536. [Google Scholar] [CrossRef] [PubMed]
  84. Bruunsgaard, H.; Andersen-Ranberg, K.; Jeune, B.; Pedersen, A.N.; Skinhøj, P.; Pedersen, B.K. A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J. Gerontol. A-Biol. 1999, 54, M357–M364. [Google Scholar] [CrossRef]
  85. Fillit, H.; Ding, W.H.; Buee, L.; Kalman, J.; Altstiel, L.; Lawlor, B.; Wolf-Klein, G. Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci. Lett. 1991, 129, 318–320. [Google Scholar] [CrossRef]
  86. Benzing, W.C.; Wujek, J.R.; Ward, E.K.; Shaffer, D.; Ashe, K.H.; Younkin, S.G.; Brunden, K.R. Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol. Aging 1999, 20, 581–589. [Google Scholar] [CrossRef]
  87. McGeer, E.G.; McGeer, P.L. Inflammatory processes in Alzheimer’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 2003, 27, 741–749. [Google Scholar] [CrossRef]
  88. Zhao, M.; Cribbs, D.H.; Anderson, A.J.; Cummings, B.J.; Su, J.H.; Wasserman, A.J.; Cotman, C.W. The induction of the TNFalpha death domain signaling pathway in Alzheimer’s disease brain. Neurochem. Res. 2003, 28, 307–318. [Google Scholar] [CrossRef] [PubMed]
  89. Koenigsknecht-Talboo, J.; Landreth, G.E. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci. 2005, 25, 8240–8249. [Google Scholar] [CrossRef] [PubMed]
  90. Yamamoto, M.; Kiyota, T.; Walsh, S.M.; Liu, J.; Kipnis, J.; Ikezu, T. Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes. J. Immunol. 2008, 181, 3877–3886. [Google Scholar] [CrossRef] [PubMed]
  91. He, P.; Zhong, Z.; Lindholm, K.; Berning, L.; Lee, W.; Lemere, C.; Staufenbiel, M.; Li, R.; Shen, Y. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J. Cell Biol. 2007, 178, 829–841. [Google Scholar] [CrossRef] [PubMed]
  92. Liao, Y.-F.; Wang, B.-J.; Cheng, H.-T.; Kuo, L.-H.; Wolfe, M.S. Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J. Biol. Chem. 2004, 279, 49523–49532. [Google Scholar] [CrossRef] [PubMed]
  93. Cheng, X.; Yang, L.; He, P.; Li, R.; Shen, Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer’s disease and non-demented patients. J. Alzheimers Dis. 2010, 19, 621–630. [Google Scholar] [PubMed]
  94. Cheng, X.; Yang, L.; He, P.; Li, R.; Shen, Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer’s disease and non-demented patients. J. Alzheimers Dis. 2010, 19, 621–630. [Google Scholar] [PubMed]
  95. Perry, R.T.; Collins, J.S.; Wiener, H.; Acton, R.; Go, R.C. The role of TNF and its receptors in Alzheimer’s disease. Neurobiol. Aging 2001, 22, 873–883. [Google Scholar] [CrossRef]
  96. Montgomery, S.L.; Mastrangelo, M.A.; Habib, D.; Narrow, W.C.; Knowlden, S.A.; Wright, T.W.; Bowers, W.J. Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: Implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain. Am. J. Pathol. 2011, 179, 2053–2070. [Google Scholar] [CrossRef] [PubMed]
  97. Montgomery, S.L.; Narrow, W.C.; Mastrangelo, M.A.; Olschowka, J.A.; O’Banion, M.K.; Bowers, W.J. Chronic neuron- and age-selective down-regulation of TNF receptor expression in triple-transgenic Alzheimer disease mice leads to significant modulation of amyloid- and Tau-related pathologies. Am. J. Pathol. 2013, 182, 2285–2297. [Google Scholar] [CrossRef] [PubMed]
  98. Jiang, H.; He, P.; Xie, J.; Staufenbiel, M.; Li, R.; Shen, Y. Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα. Hum. Mol. Genet. 2014, 23, 4906–4918. [Google Scholar] [CrossRef] [PubMed]
  99. McAlpine, F.E.; Lee, J.-K.; Harms, A.S.; Ruhn, K.A.; Blurton-Jones, M.; Hong, J.; Das, P.; Golde, T.E.; LaFerla, F.M.; Oddo, S.; et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol. Dis. 2009, 34, 163–177. [Google Scholar] [CrossRef] [PubMed]
  100. Shen, Y.; Li, R.; Shiosaki, K. Inhibition of p75 tumor necrosis factor receptor by antisense oligonucleotides increases hypoxic injury and beta-amyloid toxicity in human neuronal cell line. J. Biol. Chem. 1997, 272, 3550–3553. [Google Scholar] [CrossRef] [PubMed]
  101. Hirsch, E.C.; Vyas, S.; Hunot, S. Neuroinflammation in Parkinson’s disease. Parkinsonism Relat. Disord. 2012, 18 (Suppl. 1), S210–S212. [Google Scholar] [CrossRef]
  102. Hirsch, E.C.; Hunot, S. Neuroinflammation in Parkinson’s disease: A target for neuroprotection? Lancet Neurol. 2009, 8, 382–397. [Google Scholar] [CrossRef]
  103. McCoy, M.K.; Tansey, M.G. TNF signaling inhibition in the CNS: Implications for normal brain function and neurodegenerative disease. J. Neuroinflamm. 2008, 5, 45. [Google Scholar] [CrossRef] [PubMed]
  104. Mogi, M.; Harada, M.; Riederer, P.; Narabayashi, H.; Fujita, K.; Nagatsu, T. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 1994, 165, 208–210. [Google Scholar] [CrossRef]
  105. Mogi, M.; Togari, A.; Kondo, T.; Mizuno, Y.; Komure, O.; Kuno, S.; Ichinose, H.; Nagatsu, T. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J. Neural Transm. 2000, 107, 335–341. [Google Scholar] [CrossRef] [PubMed]
  106. Rojanathammanee, L.; Murphy, E.J.; Combs, C.K. Expression of mutant alpha-synuclein modulates microglial phenotype in vitro. J. Neuroinflamm. 2011, 8, 44. [Google Scholar] [CrossRef] [PubMed][Green Version]
  107. Su, X.; Federoff, H.J.; Maguire-Zeiss, K.A. Mutant alpha-synuclein overexpression mediates early proinflammatory activity. Neurotox. Res. 2009, 16, 238–254. [Google Scholar] [CrossRef] [PubMed]
  108. Theodore, S.; Cao, S.; McLean, P.J.; Standaert, D.G. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol. 2008, 67, 1149–1158. [Google Scholar] [CrossRef] [PubMed]
  109. Chung, C.Y.; Koprich, J.B.; Siddiqi, H.; Isacson, O. Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J. Neurosci. 2009, 29, 3365–3373. [Google Scholar] [CrossRef] [PubMed]
  110. Fischer, R.; Maier, O.; Siegemund, M.; Wajant, H.; Scheurich, P.; Pfizenmaier, K. A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death. PLoS ONE 2011, 6, e27621. [Google Scholar] [CrossRef] [PubMed]
  111. Barnum, C.J.; Chen, X.; Chung, J.; Chang, J.; Williams, M.; Grigoryan, N.; Tesi, R.J.; Tansey, M.G. Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats. J. Park. Dis. 2014, 4, 349–360. [Google Scholar]
  112. McCoy, M.K.; Martinez, T.N.; Ruhn, K.A.; Szymkowski, D.E.; Smith, C.G.; Botterman, B.R.; Tansey, K.E.; Tansey, M.G. Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J. Neurosci. 2006, 26, 9365–9375. [Google Scholar] [CrossRef] [PubMed]
  113. McCoy, M.K.; Ruhn, K.A.; Martinez, T.N.; McAlpine, F.E.; Blesch, A.; Tansey, M.G. Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol. Ther. 2008, 16, 1572–1579. [Google Scholar] [CrossRef] [PubMed]
  114. Harms, A.S.; Barnum, C.J.; Ruhn, K.A.; Varghese, S.; Treviño, I.; Blesch, A.; Tansey, M.G. Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol. Ther. 2011, 19, 46–52. [Google Scholar] [CrossRef] [PubMed]
  115. Probert, L. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience 2015, 302, 2–22. [Google Scholar] [CrossRef] [PubMed]
  116. Sriram, K.; Matheson, J.M.; Benkovic, S.A.; Miller, D.B.; Luster, M.I.; O’Callaghan, J.P. Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: Implications for Parkinson’s disease. FASEB J. 2002, 16, 1474–1476. [Google Scholar] [CrossRef] [PubMed]
  117. Dziewulska, D.; Mossakowski, M.J. Cellular expression of tumor necrosis factor a and its receptors in human ischemic stroke. Clin. Neuropathol. 2003, 22, 35–40. [Google Scholar] [PubMed]
  118. Liu, T.; Clark, R.K.; McDonnell, P.C.; Young, P.R.; White, R.F.; Barone, F.C.; Feuerstein, G.Z. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 1994, 25, 1481–1488. [Google Scholar] [CrossRef] [PubMed]
  119. Sairanen, T.; Carpén, O.; Karjalainen-Lindsberg, M.L.; Paetau, A.; Turpeinen, U.; Kaste, M.; Lindsberg, P.J. Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke 2001, 32, 1750–1758. [Google Scholar] [CrossRef] [PubMed]
  120. Tuttolomondo, A.; Di Raimondo, D.; di Sciacca, R.; Pinto, A.; Licata, G. Inflammatory cytokines in acute ischemic stroke. Curr. Pharm. Des. 2008, 14, 3574–3589. [Google Scholar] [CrossRef] [PubMed]
  121. Pan, W.; Kastin, A.J. Tumor necrosis factor and stroke: Role of the blood-brain barrier. Prog. Neurobiol. 2007, 83, 363–374. [Google Scholar] [CrossRef] [PubMed]
  122. Sumbria, R.K.; Boado, R.J.; Pardridge, W.M. Brain protection from stroke with intravenous TNFα decoy receptor-Trojan horse fusion protein. J. Cereb. Blood Flow Metab. 2012, 32, 1933–1938. [Google Scholar] [CrossRef] [PubMed]
  123. Tobinick, E.; Kim, N.M.; Reyzin, G.; Rodriguez-Romanacce, H.; DePuy, V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs 2012, 26, 1051–1070. [Google Scholar] [CrossRef] [PubMed]
  124. Wu, M.-H.; Huang, C.-C.; Chio, C.-C.; Tsai, K.-J.; Chang, C.-P.; Lin, N.-K.; Lin, M.-T. Inhibition of Peripheral TNF-α and Downregulation of Microglial Activation by Alpha-Lipoic Acid and Etanercept Protect Rat Brain Against Ischemic Stroke. Mol. Neurobiol. 2015, 1–11. [Google Scholar] [CrossRef] [PubMed]
  125. Arango-Dávila, C.A.; Vera, A.; Londoño, A.C.; Echeverri, A.F.; Cañas, F.; Cardozo, C.F.; Orozco, J.L.; Rengifo, J.; Cañas, C.A. Soluble or soluble/membrane TNF-α inhibitors protect the brain from focal ischemic injury in rats. Int. J. Neurosci. 2014, 125, 936–940. [Google Scholar] [CrossRef] [PubMed]
  126. Ding, Y.-H.; Mrizek, M.; Lai, Q.; Wu, Y.; Reyes, R.; Li, J.; Davis, W.W.; Ding, Y. Exercise preconditioning reduces brain damage and inhibits TNF-alpha receptor expression after hypoxia/reoxygenation: An in vivo and in vitro study. Curr. Neurovasc. Res. 2006, 3, 263–271. [Google Scholar] [CrossRef] [PubMed]
  127. Nawashiro, H.; Tasaki, K.; Ruetzler, C.A.; Hallenbeck, J.M. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 1997, 17, 483–490. [Google Scholar] [CrossRef] [PubMed]
  128. Botchkina, G.I.; Meistrell, M.E.; Botchkina, I.L.; Tracey, K.J. Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia. Mol. Med. Camb. Mass 1997, 3, 765–781. [Google Scholar] [PubMed]
  129. Dolga, A.M.; Nijholt, I.M.; Ostroveanu, A.; Ten Bosch, Q.; Luiten, P.G.M.; Eisel, U.L.M. Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways. J. Alzheimers Dis. 2008, 13, 111–122. [Google Scholar] [PubMed]
  130. Rasmussen, L.M.; Hansen, P.R.; Nabipour, M.T.; Olesen, P.; Kristiansen, M.T.; Ledet, T. Diverse effects of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells. Biochem. J. 2001, 360, 363–370. [Google Scholar] [CrossRef] [PubMed]
  131. Santee, S.M.; Owen-Schaub, L.B. Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization. J. Biol. Chem. 1996, 271, 21151–21159. [Google Scholar] [PubMed]
  132. Gary, D.S.; Bruce-Keller, A.J.; Kindy, M.S.; Mattson, M.P. Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J. Cereb. Blood Flow Metab. 1998, 18, 1283–1287. [Google Scholar] [CrossRef] [PubMed]
  133. Lambertsen, K.L.; Clausen, B.H.; Babcock, A.A.; Gregersen, R.; Fenger, C.; Nielsen, H.H.; Haugaard, L.S.; Wirenfeldt, M.; Nielsen, M.; Dagnaes-Hansen, F.; et al. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J. Neurosci. 2009, 29, 1319–1330. [Google Scholar] [CrossRef] [PubMed]
  134. Pradillo, J.M.; Romera, C.; Hurtado, O.; Cárdenas, A.; Moro, M.A.; Leza, J.C.; Dávalos, A.; Castillo, J.; Lorenzo, P.; Lizasoain, I. TNFR1 upregulation mediates tolerance after brain ischemic preconditioning. J. Cereb. Blood Flow Metab. 2005, 25, 193–203. [Google Scholar] [CrossRef] [PubMed]
  135. Taoufik, E.; Petit, E.; Divoux, D.; Tseveleki, V.; Mengozzi, M.; Roberts, M.L.; Valable, S.; Ghezzi, P.; Quackenbush, J.; Brines, M.; et al. TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. Proc. Natl. Acad. Sci. USA 2008, 105, 6185–6190. [Google Scholar] [CrossRef] [PubMed]
  136. Taoufik, E.; Valable, S.; Müller, G.J.; Roberts, M.L.; Divoux, D.; Tinel, A.; Voulgari-Kokota, A.; Tseveleki, V.; Altruda, F.; Lassmann, H.; et al. FLIP(L) protects neurons against in vivo ischemia and in vitro glucose deprivation-induced cell death. J. Neurosci. 2007, 27, 6633–6646. [Google Scholar] [CrossRef] [PubMed]
  137. Akassoglou, K.; Douni, E.; Bauer, J.; Lassmann, H.; Kollias, G.; Probert, L. Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice. Proc. Natl. Acad. Sci. USA 2003, 100, 709–714. [Google Scholar] [CrossRef] [PubMed]
  138. Wang, L.-W.; Chang, Y.-C.; Chen, S.-J.; Tseng, C.-H.; Tu, Y.-F.; Liao, N.-S.; Huang, C.-C.; Ho, C.-J. TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain. J. Neuroinflamm. 2014, 11, 215. [Google Scholar] [CrossRef] [PubMed]
  139. Cudrici, C.; Niculescu, T.; Niculescu, F.; Shin, M.L.; Rus, H. Oligodendrocyte cell death in pathogenesis of multiple sclerosis: Protection of oligodendrocytes from apoptosis by complement. J. Rehabil. Res. Dev. 2006, 43, 123–132. [Google Scholar] [CrossRef] [PubMed]
  140. Hofman, F.M.; Hinton, D.R.; Johnson, K.; Merrill, J.E. Tumor necrosis factor identified in multiple sclerosis brain. J. Exp. Med. 1989, 170, 607–612. [Google Scholar] [CrossRef] [PubMed]
  141. Selmaj, K.; Raine, C.S.; Cannella, B.; Brosnan, C.F. Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J. Clin. Invest. 1991, 87, 949–954. [Google Scholar] [CrossRef] [PubMed]
  142. Probert, L.; Akassoglou, K.; Pasparakis, M.; Kontogeorgos, G.; Kollias, G. Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc. Natl. Acad. Sci. USA 1995, 92, 11294–11298. [Google Scholar] [CrossRef] [PubMed]
  143. Yang, G.; Parkhurst, C.N.; Hayes, S.; Gan, W.-B. Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 2013, 110, 10306–10311. [Google Scholar] [CrossRef] [PubMed]
  144. Constantinescu, C.S.; Farooqi, N.; O’Brien, K.; Gran, B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br. J. Pharmacol. 2011, 164, 1079–1106. [Google Scholar] [CrossRef] [PubMed]
  145. Liu, J.; Marino, M.W.; Wong, G.; Grail, D.; Dunn, A.; Bettadapura, J.; Slavin, A.J.; Old, L.; Bernard, C.C. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat. Med. 1998, 4, 78–83. [Google Scholar] [CrossRef] [PubMed]
  146. Arnett, H.A.; Mason, J.; Marino, M.; Suzuki, K.; Matsushima, G.K.; Ting, J.P. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci. 2001, 4, 1116–1122. [Google Scholar] [CrossRef] [PubMed]
  147. Akassoglou, K.; Bauer, J.; Kassiotis, G.; Pasparakis, M.; Lassmann, H.; Kollias, G.; Probert, L. Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. Am. J. Pathol. 1998, 153, 801–813. [Google Scholar] [CrossRef]
  148. Gimenez, M.A.; Sim, J.; Archambault, A.S.; Klein, R.S.; Russell, J.H. A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. Am. J. Pathol. 2006, 168, 1200–1209. [Google Scholar] [CrossRef] [PubMed]
  149. Nomura, T.; Abe, Y.; Kamada, H.; Shibata, H.; Kayamuro, H.; Inoue, M.; Kawara, T.; Arita, S.; Furuya, T.; Yamashita, T.; et al. Therapeutic effect of PEGylated TNFR1-selective antagonistic mutant TNF in experimental autoimmune encephalomyelitis mice. J. Control. Release 2011, 149, 8–14. [Google Scholar] [CrossRef] [PubMed]
  150. Taoufik, E.; Tseveleki, V.; Chu, S.Y.; Tselios, T.; Karin, M.; Lassmann, H.; Szymkowski, D.E.; Probert, L. Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-kappaB. Brain J. Neurol. 2011, 134, 2722–2735. [Google Scholar] [CrossRef] [PubMed]
  151. Brambilla, R.; Ashbaugh, J.J.; Magliozzi, R.; Dellarole, A.; Karmally, S.; Szymkowski, D.E.; Bethea, J.R. Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain J. Neurol. 2011, 134, 2736–2754. [Google Scholar] [CrossRef] [PubMed]
  152. Eugster, H.P.; Frei, K.; Bachmann, R.; Bluethmann, H.; Lassmann, H.; Fontana, A. Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur. J. Immunol. 1999, 29, 626–632. [Google Scholar] [CrossRef]
  153. Suvannavejh, G.C.; Lee, H.O.; Padilla, J.; Dal Canto, M.C.; Barrett, T.A.; Miller, S.D. Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenesis of MOG(35-55)-induced experimental autoimmune encephalomyelitis. Cell. Immunol. 2000, 205, 24–33. [Google Scholar] [CrossRef] [PubMed]
  154. Kassiotis, G.; Kollias, G. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: Implications for pathogenesis and therapy of autoimmune demyelination. J. Exp. Med. 2001, 193, 427–434. [Google Scholar] [CrossRef] [PubMed]
  155. Maier, O.; Fischer, R.; Agresti, C.; Pfizenmaier, K. TNF receptor 2 protects oligodendrocyte progenitor cells against oxidative stress. Biochem. Biophys. Res. Commun. 2013, 440, 336–341. [Google Scholar] [CrossRef] [PubMed]
  156. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter study. Neurology 1999, 53, 457–465. [Google Scholar]
  157. Pfueller, C.F.; Seipelt, E.; Zipp, F.; Paul, F. Multiple sclerosis following etanercept treatment for ankylosing spondylitis. Scand. J. Rheumatol. 2008, 37, 397–399. [Google Scholar] [CrossRef] [PubMed]
  158. Sicotte, N.L.; Voskuhl, R.R. Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 2001, 57, 1885–1888. [Google Scholar] [CrossRef] [PubMed]
  159. Jiang, H.; Hampel, H.; Prvulovic, D.; Wallin, A.; Blennow, K.; Li, R.; Shen, Y. Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer’s disease. Mol. Neurodegener. 2011, 6, 69. [Google Scholar] [CrossRef] [PubMed]
  160. Bai, L.; Song, N.; Yu, J.; Tan, L.; Shen, Y.; Xie, J.; Jiang, H. Elevated plasma levels of soluble TNFRs and TACE activity in Alzheimer’s disease patients of Northern Han Chinese descent. Curr. Alzheimer Res. 2013, 10, 57–62. [Google Scholar] [PubMed]
  161. Diniz, B.S.; Teixeira, A.L.; Ojopi, E.B.; Talib, L.L.; Mendonça, V.A.; Gattaz, W.F.; Forlenza, O.V. Higher serum sTNFR1 level predicts conversion from mild cognitive impairment to Alzheimer’s disease. J. Alzheimers Dis. 2010, 22, 1305–1311. [Google Scholar] [PubMed]
  162. Faria, M.C.; Gonçalves, G.S.; Rocha, N.P.; Moraes, E.N.; Bicalho, M.A.; Gualberto Cintra, M.T.; Jardim de Paula, J.; José Ravic de Miranda, L.F.; Clayton de Souza Ferreira, A.; Teixeira, A.L.; et al. Increased plasma levels of BDNF and inflammatory markers in Alzheimer’s disease. J. Psychiatr. Res. 2014, 53, 166–172. [Google Scholar] [CrossRef] [PubMed]
  163. Sun, Q.; Hampel, H.; Blennow, K.; Lista, S.; Levey, A.; Tang, B.; Li, R.; Shen, Y. Increased plasma TACE activity in subjects with mild cognitive impairment and patients with Alzheimer’s disease. J. Alzheimers Dis. 2014, 41, 877–886. [Google Scholar] [PubMed]
  164. Buchhave, P.; Zetterberg, H.; Blennow, K.; Minthon, L.; Janciauskiene, S.; Hansson, O. Soluble TNF receptors are associated with Aβ metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiol. Aging 2010, 31, 1877–1884. [Google Scholar] [CrossRef] [PubMed]
  165. Scalzo, P.; Kümmer, A.; Cardoso, F.; Teixeira, A.L. Increased serum levels of soluble tumor necrosis factor-alpha receptor-1 in patients with Parkinson’s disease. J. Neuroimmunol. 2009, 216, 122–125. [Google Scholar] [CrossRef] [PubMed]
  166. Rocha, N.P.; Teixeira, A.L.; Scalzo, P.L.; Barbosa, I.G.; de Sousa, M.S.; Morato, I.B.; Vieira, E.L.M.; Christo, P.P.; Palotás, A.; Reis, H.J. Plasma levels of soluble tumor necrosis factor receptors are associated with cognitive performance in Parkinson’s disease. Mov. Disord. 2014, 29, 527–531. [Google Scholar] [CrossRef] [PubMed]
  167. Woodcock, T.; Morganti-Kossmann, C. The role of markers of inflammation in traumatic brain injury. Neurotrauma 2013, 4, 18. [Google Scholar] [CrossRef] [PubMed]
  168. Li, G.; Bauer, S.; Nowak, M.; Norwood, B.; Tackenberg, B.; Rosenow, F.; Knake, S.; Oertel, W.H.; Hamer, H.M. Cytokines and epilepsy. Seizure 2011, 20, 249–256. [Google Scholar] [CrossRef] [PubMed]
  169. Ellrichmann, G.; Reick, C.; Saft, C.; Linker, R.A.; Ellrichmann, G.; Reick, C.; Saft, C.; Linker, R.A. The Role of the Immune System in Huntington's Disease. J. Immunol. Res. 2013, 2013, e541259. [Google Scholar] [CrossRef] [PubMed]
  170. Alto, L.T.; Chen, X.; Ruhn, K.A.; Treviño, I.; Tansey, M.G. AAV-Dominant Negative Tumor Necrosis Factor (DN-TNF) Gene Transfer to the Striatum Does Not Rescue Medium Spiny Neurons in the YAC128 Mouse Model of Huntington’s Disease. PLoS ONE 2014, 9, e96544. [Google Scholar] [CrossRef] [PubMed]
  171. Longhi, L.; Ortolano, F.; Zanier, E.R.; Perego, C.; Stocchetti, N.; De Simoni, M.G. Effect of traumatic brain injury on cognitive function in mice lacking p55 and p75 tumor necrosis factor receptors. Acta Neurochir. Suppl. 2008, 102, 409–413. [Google Scholar] [PubMed]
  172. Longhi, L.; Perego, C.; Ortolano, F.; Aresi, S.; Fumagalli, S.; Zanier, E.R.; Stocchetti, N.; De Simoni, M.-G. Tumor necrosis factor in traumatic brain injury: Effects of genetic deletion of p55 or p75 receptor. J. Cereb. Blood Flow Metab. 2013, 33, 1182–1189. [Google Scholar] [CrossRef] [PubMed]
  173. Thompson, S.J.; Ashley, M.D.; Stöhr, S.; Schindler, C.; Li, M.; McCarthy-Culpepper, K.A.; Pearson, A.N.; Xiong, Z.-G.; Simon, R.P.; Henshall, D.C.; et al. Suppression of TNF receptor-1 signaling in an in vitro model of epileptic tolerance. Int. J. Physiol. Pathophysiol. Pharmacol. 2011, 3, 120–132. [Google Scholar] [PubMed]
  174. Balosso, S.; Ravizza, T.; Perego, C.; Peschon, J.; Campbell, I.L.; De Simoni, M.G.; Vezzani, A. Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors. Ann. Neurol. 2005, 57, 804–812. [Google Scholar] [CrossRef] [PubMed]
  175. Hsiao, H.-Y.; Chiu, F.-L.; Chen, C.-M.; Wu, Y.-R.; Chen, H.-M.; Chen, Y.-C.; Kuo, H.-C.; Chern, Y. Inhibition of soluble tumor necrosis factor is therapeutic in Huntington’s disease. Hum. Mol. Genet. 2014, 23, 4328–4344. [Google Scholar] [CrossRef] [PubMed]
  176. Neufeld, E.F. Lysosomal storage diseases. Annu. Rev. Biochem. 1991, 60, 257–280. [Google Scholar] [CrossRef] [PubMed]
  177. Platt, F.M.; Boland, B.; van der Spoel, A.C. The cell biology of disease: Lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J. Cell Biol. 2012, 199, 723–734. [Google Scholar] [CrossRef] [PubMed]
  178. German, D.C.; Liang, C.-L.; Song, T.; Yazdani, U.; Xie, C.; Dietschy, J.M. Neurodegeneration in the Niemann–Pick C mouse: Glial involvement. Neuroscience 2002, 109, 437–450. [Google Scholar] [CrossRef]
  179. Patel, S.C.; Suresh, S.; Kumar, U.; Hu, C.Y.; Cooney, A.; Blanchette-Mackie, E.J.; Neufeld, E.B.; Patel, R.C.; Brady, R.O.; Patel, Y.C.; et al. Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease. Proc. Natl. Acad. Sci. USA 1999, 96, 1657–1662. [Google Scholar] [CrossRef] [PubMed]
  180. Wu, Y.-P.; Mizukami, H.; Matsuda, J.; Saito, Y.; Proia, R.L.; Suzuki, K. Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease. Mol. Genet. Metab. 2005, 84, 9–17. [Google Scholar] [CrossRef] [PubMed]
  181. Hong, Y.B.; Kim, E.Y.; Jung, S.-C. Upregulation of proinflammatory cytokines in the fetal brain of the Gaucher mouse. J. Korean Med. Sci. 2006, 21, 733–738. [Google Scholar] [CrossRef] [PubMed]
  182. Barak, V.; Acker, M.; Nisman, B.; Kalickman, I.; Abrahamov, A.; Zimran, A.; Yatziv, S. Cytokines in Gaucher’s disease. Eur. Cytokine Netw. 1999, 10, 205–210. [Google Scholar] [PubMed]
  183. Vitner, E.B.; Farfel-Becker, T.; Eilam, R.; Biton, I.; Futerman, A.H. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain J. Neurol. 2012, 135, 1724–1735. [Google Scholar] [CrossRef] [PubMed]
  184. Naudé, P.J.W.; Nyakas, C.; Eiden, L.E.; Ait-Ali, D.; van der Heide, R.; Engelborghs, S.; Luiten, P.G.M.; De Deyn, P.P.; den Boer, J.A.; Eisel, U.L.M. Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer’s disease. FASEB J. 2012, 26, 2811–2823. [Google Scholar] [CrossRef] [PubMed]
  185. Goetz, D.H.; Holmes, M.A.; Borregaard, N.; Bluhm, M.E.; Raymond, K.N.; Strong, R.K. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 2002, 10, 1033–1043. [Google Scholar] [CrossRef]
  186. Marques, F.; Mesquita, S.D.; Sousa, J.C.; Coppola, G.; Gao, F.; Geschwind, D.H.; Columba-Cabezas, S.; Aloisi, F.; Degn, M.; Cerqueira, J.J.; et al. Lipocalin 2 is present in the EAE brain and is modulated by natalizumab. Front. Cell. Neurosci. 2012, 6, 33. [Google Scholar] [CrossRef] [PubMed][Green Version]
  187. Wang, G.; Weng, Y.-C.; Han, X.; Whaley, J.D.; McCrae, K.R.; Chou, W.-H. Lipocalin-2 released in response to cerebral ischaemia mediates reperfusion injury in mice. J. Cell. Mol. Med. 2015, 19, 1637–1645. [Google Scholar] [CrossRef] [PubMed]
  188. Bi, F.; Huang, C.; Tong, J.; Qiu, G.; Huang, B.; Wu, Q.; Li, F.; Xu, Z.; Bowser, R.; Xia, X.-G.; et al. Reactive astrocytes secrete lcn2 to promote neuron death. Proc. Natl. Acad. Sci. USA 2013, 110, 4069–4074. [Google Scholar] [CrossRef] [PubMed]
  189. Lee, S.; Lee, W.-H.; Lee, M.-S.; Mori, K.; Suk, K. Regulation by lipocalin-2 of neuronal cell death, migration, and morphology. J. Neurosci. Res. 2012, 90, 540–550. [Google Scholar] [CrossRef] [PubMed]
  190. Mesquita, S.D.; Ferreira, A.C.; Falcao, A.M.; Sousa, J.C.; Oliveira, T.G.; Correia-Neves, M.; Sousa, N.; Marques, F.; Palha, J.A. Lipocalin 2 modulates the cellular response to amyloid beta. Cell Death Differ. 2014, 21, 1588–1599. [Google Scholar] [CrossRef] [PubMed][Green Version]
  191. Jang, E.; Kim, J.-H.; Lee, S.; Kim, J.-H.; Seo, J.-W.; Jin, M.; Lee, M.-G.; Jang, I.-S.; Lee, W.-H.; Suk, K. Phenotypic polarization of activated astrocytes: The critical role of lipocalin-2 in the classical inflammatory activation of astrocytes. J. Immunol. 2013, 191, 5204–5219. [Google Scholar] [CrossRef] [PubMed]
  192. Jang, E.; Lee, S.; Kim, J.-H.; Kim, J.-H.; Seo, J.-W.; Lee, W.-H.; Mori, K.; Nakao, K.; Suk, K. Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J. 2013, 27, 1176–1190. [Google Scholar] [CrossRef] [PubMed]
  193. Lee, I.-T.; Lin, C.-C.; Wu, Y.-C.; Yang, C.-M. TNF-alpha induces matrix metalloproteinase-9 expression in A549 cells: role of TNFR1/TRAF2/PKCalpha-dependent signaling pathways. J. Cell. Physiol. 2010, 224, 454–464. [Google Scholar] [CrossRef] [PubMed]
  194. Tsai, C.-L.; Chen, W.-C.; Hsieh, H.-L.; Chi, P.-L.; Hsiao, L.-D.; Yang, C.-M. TNF-α induces matrix metalloproteinase-9-dependent soluble intercellular adhesion molecule-1 release via TRAF2-mediated MAPKs and NF-κB activation in osteoblast-like MC3T3-E1 cells. J. Biomed. Sci. 2014, 21, 12. [Google Scholar] [CrossRef] [PubMed]
  195. Lin, C.-C.; Tseng, H.-W.; Hsieh, H.-L.; Lee, C.-W.; Wu, C.-Y.; Cheng, C.-Y.; Yang, C.-M. Tumor necrosis factor-alpha induces MMP-9 expression via p42/p44 MAPK, JNK, and nuclear factor-kappaB in A549 cells. Toxicol. Appl. Pharmacol. 2008, 229, 386–398. [Google Scholar] [CrossRef] [PubMed]
  196. Lakhan, S.E.; Kirchgessner, A.; Tepper, D.; Leonard, A. Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke. Front. Neurol. 2013, 4, 1–15. [Google Scholar] [CrossRef] [PubMed]
  197. Mizoguchi, H.; Takuma, K.; Fukuzaki, E.; Ibi, D.; Someya, E.; Akazawa, K.; Alkam, T.; Tsunekawa, H.; Mouri, A.; Noda, Y.; et al. Matrix metalloprotease-9 inhibition improves amyloid beta-mediated cognitive impairment and neurotoxicity in mice. J. Pharmacol. Exp. Ther. 2009, 331, 14–22. [Google Scholar] [CrossRef] [PubMed]
  198. Takata, F.; Dohgu, S.; Matsumoto, J.; Takahashi, H.; Machida, T.; Wakigawa, T.; Harada, E.; Miyaji, H.; Koga, M.; Nishioku, T.; et al. Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-α, releasing matrix metalloproteinase-9 and migrating in vitro. J. Neuroinflamm. 2011, 8, 106. [Google Scholar] [CrossRef] [PubMed]
  199. Yan, P.; Hu, X.; Song, H.; Yin, K.; Bateman, R.J.; Cirrito, J.R.; Xiao, Q.; Hsu, F.F.; Turk, J.W.; Xu, J.; et al. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J. Biol. Chem. 2006, 281, 24566–24574. [Google Scholar] [CrossRef] [PubMed]
  200. Yan, L.; Borregaard, N.; Kjeldsen, L.; Moses, M.A. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J. Biol. Chem. 2001, 276, 37258–37265. [Google Scholar] [CrossRef] [PubMed]
  201. He, P.; Liu, Q.; Wu, J.; Shen, Y. Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons. FASEB J. 2012, 26, 334–345. [Google Scholar] [CrossRef] [PubMed]
  202. Bezzi, P.; Domercq, M.; Brambilla, L.; Galli, R.; Schols, D.; De Clercq, E.; Vescovi, A.; Bagetta, G.; Kollias, G.; Meldolesi, J.; et al. CXCR4-activated astrocyte glutamate release via TNFalpha: Amplification by microglia triggers neurotoxicity. Nat. Neurosci. 2001, 4, 702–710. [Google Scholar] [CrossRef] [PubMed]
  203. Takeuchi, H.; Jin, S.; Wang, J.; Zhang, G.; Kawanokuchi, J.; Kuno, R.; Sonobe, Y.; Mizuno, T.; Suzumura, A. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J. Biol. Chem. 2006, 281, 21362–21368. [Google Scholar] [CrossRef] [PubMed]
  204. Olmos, G.; Lladó, J. Tumor necrosis factor alpha: A link between neuroinflammation and excitotoxicity. Mediat. Inflamm. 2014, 2014, 861231. [Google Scholar] [CrossRef] [PubMed]
  205. Dolga, A.M.; Terpolilli, N.; Kepura, F.; Nijholt, I.M.; Knaus, H.-G.; D’Orsi, B.; Prehn, J.H.M.; Eisel, U.L.M.; Plant, T.; Plesnila, N.; et al. KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia. Cell Death Dis. 2011, 2, e147. [Google Scholar] [CrossRef] [PubMed]
  206. Kuiper, E.F.E.; Nelemans, A.; Luiten, P.; Nijholt, I.; Dolga, A.; Eisel, U. K(Ca)2 and k(ca)3 channels in learning and memory processes, and neurodegeneration. Front. Pharmacol. 2012, 3, 107. [Google Scholar] [CrossRef] [PubMed]
  207. Allen, D.; Bond, C.T.; Luján, R.; Ballesteros-Merino, C.; Lin, M.T.; Wang, K.; Klett, N.; Watanabe, M.; Shigemoto, R.; Stackman, R.W.; et al. The SK2-long isoform directs synaptic localization and function of SK2-containing channels. Nat. Neurosci. 2011, 14, 744–749. [Google Scholar] [CrossRef] [PubMed]
  208. Fischer, R.; Wajant, H.; Kontermann, R.; Pfizenmaier, K.; Maier, O. Astrocyte-specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor. Glia 2014, 62, 272–283. [Google Scholar] [CrossRef] [PubMed]
  209. Moidunny, S.; Vinet, J.; Wesseling, E.; Bijzet, J.; Shieh, C.-H.; van Ijzendoorn, S.C.D.; Bezzi, P.; Boddeke, H.W.G.M.; Biber, K. Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity. J. Neuroinflamm. 2012, 9, 198. [Google Scholar] [CrossRef] [PubMed][Green Version]
  210. Gresle, M.M.; Alexandrou, E.; Wu, Q.; Egan, G.; Jokubaitis, V.; Ayers, M.; Jonas, A.; Doherty, W.; Friedhuber, A.; Shaw, G.; et al. Leukemia inhibitory factor protects axons in experimental autoimmune encephalomyelitis via an oligodendrocyte-independent mechanism. PLoS ONE 2012, 7, e47379. [Google Scholar] [CrossRef] [PubMed]
  211. Patel, J.R.; Williams, J.L.; Muccigrosso, M.M.; Liu, L.; Sun, T.; Rubin, J.B.; Klein, R.S. Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. Acta Neuropathol. 2012, 124, 847–860. [Google Scholar] [CrossRef] [PubMed]
  212. Parachikova, A.; Cotman, C.W. Reduced CXCL12/CXCR4 results in impaired learning and is downregulated in a mouse model of Alzheimer disease. Neurobiol. Dis. 2007, 28, 143–153. [Google Scholar] [CrossRef] [PubMed]
  213. Veroni, C.; Gabriele, L.; Canini, I.; Castiello, L.; Coccia, E.; Remoli, M.E.; Columba-Cabezas, S.; Aricò, E.; Aloisi, F.; Agresti, C. Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways. Mol. Cell. Neurosci. 2010, 45, 234–244. [Google Scholar] [CrossRef] [PubMed]
  214. Fischer, R.; Kontermann, R.E.; Maier, O. Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy. Antibodies 2015, 4, 48–70. [Google Scholar] [CrossRef]
  215. Rodriguez, M.; Zoecklein, L.; Papke, L.; Gamez, J.; Denic, A.; Macura, S.; Howe, C. Tumor necrosis factor alpha is reparative via TNFR2 [corrected] in the hippocampus and via TNFR1 [corrected] in the striatum after virus-induced encephalitis. Brain Pathol. 2009, 19, 12–26. [Google Scholar] [CrossRef] [PubMed]
  216. Sriram, K.; Matheson, J.M.; Benkovic, S.A.; Miller, D.B.; Luster, M.I.; O’Callaghan, J.P. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: Role of TNF-alpha. FASEB J. 2006, 20, 670–682. [Google Scholar] [CrossRef] [PubMed]
  217. Wilde, G.J.; Pringle, A.K.; Sundstrom, L.E.; Mann, D.A.; Iannotti, F. Attenuation and augmentation of ischaemia-related neuronal death by tumour necrosis factor-alpha in vitro. Eur. J. Neurosci. 2000, 12, 3863–3870. [Google Scholar] [CrossRef] [PubMed]
  218. Kuno, R.; Yoshida, Y.; Nitta, A.; Nabeshima, T.; Wang, J.; Sonobe, Y.; Kawanokuchi, J.; Takeuchi, H.; Mizuno, T.; Suzumura, A. The role of TNF-alpha and its receptors in the production of NGF and GDNF by astrocytes. Brain Res. 2006, 1116, 12–18. [Google Scholar] [CrossRef] [PubMed]
  219. Lucas, R.; Lou, J.; Morel, D.R.; Ricou, B.; Suter, P.M.; Grau, G.E. TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria. J. Leuk. Biol. 1997, 61, 551–558. [Google Scholar] [CrossRef]
  220. Pola, R.; Flex, A.; Gaetani, E.; Santoliquido, A.; Serricchio, M.; Pola, P.; Bernabei, R. Intercellular adhesion molecule-1 K469E gene polymorphism and Alzheimer’s disease. Neurobiol. Aging 2003, 24, 385–387. [Google Scholar] [CrossRef]
  221. Hattori, A.; Hayashi, K.; Kohno, M. Tumor necrosis factor (TNF) stimulates the production of nerve growth factor in fibroblasts via the 55-kDa type 1 TNF receptor. FEBS Lett. 1996, 379, 157–160. [Google Scholar] [CrossRef]
  222. Dopp, J.M.; Mackenzie-Graham, A.; Otero, G.C.; Merrill, J.E. Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia. J. Neuroimmunol. 1997, 75, 104–112. [Google Scholar] [CrossRef]
  223. Etemadi, N.; Holien, J.K.; Chau, D.; Dewson, G.; Murphy, J.M.; Alexander, W.S.; Parker, M.W.; Silke, J.; Nachbur, U. Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor. FEBS J. 2013, 280, 5283–5297. [Google Scholar] [CrossRef] [PubMed]
  224. Hawari, F.I.; Rouhani, F.N.; Cui, X.; Yu, Z.-X.; Buckley, C.; Kaler, M.; Levine, S.J. Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors. Proc. Natl. Acad. Sci. USA 2004, 101, 1297–1302. [Google Scholar] [CrossRef] [PubMed]
  225. Diez-Ruiz, A.; Tilz, G.P.; Zangerle, R.; Baier-Bitterlich, G.; Wachter, H.; Fuchs, D. Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. Eur. J. Haematol. 1995, 54, 1–8. [Google Scholar] [CrossRef] [PubMed]
  226. Jansen, J.; van der Poll, T.; Levi, M.; ten Cate, H.; Gallati, H.; ten Cate, J.W.; van Deventer, S.J. Inhibition of the release of soluble tumor necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor-alpha antibody. J. Clin. Immunol. 1995, 15, 45–50. [Google Scholar] [CrossRef] [PubMed]
  227. Gregory, A.P.; Dendrou, C.A.; Attfield, K.E.; Haghikia, A.; Xifara, D.K.; Butter, F.; Poschmann, G.; Kaur, G.; Lambert, L.; Leach, O.A.; et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 2012, 488, 508–511. [Google Scholar] [CrossRef] [PubMed]
  228. Eissner, G.; Kolch, W.; Scheurich, P. Ligands working as receptors: Reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev. 2004, 15, 353–366. [Google Scholar] [CrossRef] [PubMed]
  229. Sipos, O.; Török, A.; Kalic, T.; Duda, E.; Filkor, K. Reverse Signaling Contributes to Control of Chronic Inflammation by Anti-TNF Therapeutics. Antibodies 2015, 4, 123–140. [Google Scholar] [CrossRef]
  230. Waetzig, G.H.; Rosenstiel, P.; Arlt, A.; Till, A.; Bräutigam, K.; Schäfer, H.; Rose-John, S.; Seegert, D.; Schreiber, S. Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor-beta1. FASEB J. 2005, 19, 91–93. [Google Scholar] [PubMed]
  231. Kisiswa, L.; Osório, C.; Erice, C.; Vizard, T.; Wyatt, S.; Davies, A.M. TNFα reverse signaling promotes sympathetic axon growth and target innervation. Nat. Neurosci. 2013, 16, 865–873. [Google Scholar] [CrossRef] [PubMed]
  232. Meusch, U.; Rossol, M.; Baerwald, C.; Hauschildt, S.; Wagner, U. Outside-to-inside signaling through transmembrane tumor necrosis factor reverses pathologic interleukin-1beta production and deficient apoptosis of rheumatoid arthritis monocytes. Arthritis Rheum. 2009, 60, 2612–2621. [Google Scholar] [CrossRef] [PubMed]
  233. Kirchner, S.; Holler, E.; Haffner, S.; Andreesen, R.; Eissner, G. Effect of different tumor necrosis factor (TNF) reactive agents on reverse signaling of membrane integrated TNF in monocytes. Cytokine 2004, 28, 67–74. [Google Scholar] [CrossRef] [PubMed]
  234. Cui, X.; Hawari, F.; Alsaaty, S.; Lawrence, M.; Combs, C.A.; Geng, W.; Rouhani, F.N.; Miskinis, D.; Levine, S.J. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J. Clin. Invest. 2002, 110, 515–526. [Google Scholar] [CrossRef] [PubMed]
  235. Islam, A.; Adamik, B.; Hawari, F.I.; Ma, G.; Rouhani, F.N.; Zhang, J.; Levine, S.J. Extracellular TNFR1 release requires the calcium-dependent formation of a nucleobindin 2-ARTS-1 complex. J. Biol. Chem. 2006, 281, 6860–6873. [Google Scholar] [CrossRef] [PubMed]
  236. Cui, X.; Rouhani, F.N.; Hawari, F.; Levine, S.J. Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J. Immunol. 2003, 171, 6814–6819. [Google Scholar] [CrossRef] [PubMed]
  237. Yang, S.; Wang, Y.; Mei, K.; Zhang, S.; Sun, X.; Ren, F.; Liu, S.; Yang, Z.; Wang, X.; Qin, Z.; et al. Tumor necrosis factor receptor 2 (TNFR2)·interleukin-17 receptor D (IL-17RD) heteromerization reveals a novel mechanism for NF-κB activation. J. Biol. Chem. 2015, 290, 861–871. [Google Scholar] [CrossRef] [PubMed]
  238. Mease, P. Psoriatic arthritis: The role of TNF inhibition and the effect of its inhibition with etanercept. Clin. Exp. Rheumatol. 2002, 20, S116–121. [Google Scholar] [PubMed]
  239. Liu, Y.; Yang, G.; Zhang, J.; Xing, K.; Dai, L.; Cheng, L.; Liu, J.; Deng, J.; Shi, G.; Li, C.; et al. Anti-TNF-α monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis. Int. Immunopharmacol. 2015, 28, 731–743. [Google Scholar] [CrossRef] [PubMed]
  240. McAlpine, F.E.; Lee, J.-K.; Harms, A.S.; Ruhn, K.A.; Blurton-Jones, M.; Hong, J.; Das, P.; Golde, T.E.; LaFerla, F.M.; Oddo, S.; et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol. Dis. 2009, 34, 163–177. [Google Scholar] [CrossRef] [PubMed]
  241. Spinelli, F.R.; Di Franco, M.; Metere, A.; Conti, F.; Iannuccelli, C.; Agati, L.; Valesini, G. Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis. Drug Dev. Res. 2014, 75 (Suppl. 1), S67–S69. [Google Scholar] [CrossRef] [PubMed]
  242. Bernardes, C.; Carvalho, D.; Russo, P.; Saiote, J.; Ramos, J. Anti-TNF alpha therapy in Inflammatory Bowel Disease - safety profile in elderly patients. J. Crohns Colitis 2015, 9 (Suppl. 1), S400. [Google Scholar]
  243. Maini, R.N.; Taylor, P.C. Anti-cytokine therapy for rheumatoid arthritis. Annu. Rev. Med. 2000, 51, 207–229. [Google Scholar] [CrossRef] [PubMed]
  244. Tweedie, D.; Sambamurti, K.; Greig, N.H. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: New drug candidates and targets. Curr. Alzheimer Res. 2007, 4, 378–385. [Google Scholar] [CrossRef] [PubMed]
  245. Greig, N.H.; Mattson, M.P.; Perry, T.; Chan, S.L.; Giordano, T.; Sambamurti, K.; Rogers, J.T.; Ovadia, H.; Lahiri, D.K. New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists. Ann. NY Acad. Sci. 2004, 1035, 290–315. [Google Scholar] [CrossRef] [PubMed]
  246. Zhu, X.; Giordano, T.; Yu, Q.-S.; Holloway, H.W.; Perry, T.A.; Lahiri, D.K.; Brossi, A.; Greig, N.H. Thiothalidomides: Novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. J. Med. Chem. 2003, 46, 5222–5229. [Google Scholar] [CrossRef] [PubMed]
  247. Sfikakis, P.P. The first decade of biologic TNF antagonists in clinical practice: Lessons learned, unresolved issues and future directions. Curr. Dir. Autoimmun. 2010, 11, 180–210. [Google Scholar] [PubMed]
  248. Hyrich, K.L.; Lunt, M.; Watson, K.D.; Symmons, D.P.M.; Silman, A.J. British Society for Rheumatology Biologics Register Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007, 56, 13–20. [Google Scholar] [PubMed]
  249. Atzeni, F.; Gianturco, L.; Talotta, R.; Varisco, V.; Ditto, M.C.; Turiel, M.; Sarzi-Puttini, P. Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: Cause for concern? Immunotherapy 2015, 7, 353–361. [Google Scholar] [CrossRef] [PubMed]
  250. Beigel, F.; Steinborn, A.; Schnitzler, F.; Tillack, C.; Breiteneicher, S.; John, J.M.; Van Steen, K.; Laubender, R.P.; Göke, B.; Seiderer, J.; et al. Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies. Pharmacoepidemiol. Drug Saf. 2014, 23, 735–744. [Google Scholar] [CrossRef] [PubMed]
  251. Richez, C.; Blanco, P.; Lagueny, A.; Schaeverbeke, T.; Dehais, J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology 2005, 64, 1468–1470. [Google Scholar] [CrossRef] [PubMed]
  252. Guiddir, T.; Frémond, M.-L.; Triki, T.B.; Candon, S.; Croisille, L.; Leblanc, T.; de Pontual, L. Anti-TNF-α therapy may cause neonatal neutropenia. Pediatrics 2014, 134, e1189–e1193. [Google Scholar] [CrossRef] [PubMed]
  253. Sedger, L.M.; Osvath, S.R.; Xu, X.-M.; Li, G.; Chan, F.K.-M.; Barrett, J.W.; McFadden, G. Poxvirus tumor necrosis factor receptor (TNFR)-like T2 proteins contain a conserved preligand assembly domain that inhibits cellular TNFR1-induced cell death. J. Virol. 2006, 80, 9300–9309. [Google Scholar] [CrossRef] [PubMed]
  254. Shibata, H.; Yoshioka, Y.; Ohkawa, A.; Minowa, K.; Mukai, Y.; Abe, Y.; Taniai, M.; Nomura, T.; Kayamuro, H.; Nabeshi, H.; et al. Creation and X-ray structure analysis of the tumor necrosis factor receptor-1-selective mutant of a tumor necrosis factor-alpha antagonist. J. Biol. Chem. 2008, 283, 998–1007. [Google Scholar] [CrossRef] [PubMed]
  255. Richter, F.; Liebig, T.; Guenzi, E.; Herrmann, A.; Scheurich, P.; Pfizenmaier, K.; Kontermann, R.E. Antagonistic TNF receptor one-specific antibody (ATROSAB): receptor binding and in vitro bioactivity. PLoS ONE 2013, 8, e72156. [Google Scholar] [CrossRef] [PubMed]
  256. Zettlitz, K.A.; Lorenz, V.; Landauer, K.; Münkel, S.; Herrmann, A.; Scheurich, P.; Pfizenmaier, K.; Kontermann, R. ATROSAB, a humanized antagonistic anti-tumor necrosis factor receptor one-specific antibody. mAbs 2010, 2, 639–647. [Google Scholar] [CrossRef] [PubMed]
  257. Novrup, H.G.; Bracchi-Ricard, V.; Ellman, D.G.; Ricard, J.; Jain, A.; Runko, E.; Lyck, L.; Yli-Karjanmaa, M.; Szymkowski, D.E.; Pearse, D.D.; et al. Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice. J. Neuroinflamm. 2014, 11, 159. [Google Scholar] [CrossRef] [PubMed][Green Version]
  258. Barnum, C.J.; Chen, X.; Chung, J.; Chang, J.; Williams, M.; Grigoryan, N.; Tesi, R.J.; Tansey, M.G. Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats. J. Park. Dis. 2014, 4, 349–360. [Google Scholar]
  259. Deng, M.; Loughran, P.A.; Zhang, L.; Scott, M.J.; Billiar, T.R. Shedding of the tumor necrosis factor (TNF) receptor from the surface of hepatocytes during sepsis limits inflammation through cGMP signaling. Sci. Signal. 2015, 8, ra11. [Google Scholar] [CrossRef] [PubMed]
  260. Nübel, T.; Schmitt, S.; Kaina, B.; Fritz, G. Lovastatin stimulates p75 TNF receptor (TNFR2) expression in primary human endothelial cells. Int. J. Mol. Med. 2005, 16, 1139–1145. [Google Scholar] [CrossRef] [PubMed]
  261. Dolga, A.M.; Nijholt, I.M.; Ostroveanu, A.; Ten Bosch, Q.; Luiten, P.G.M.; Eisel, U.L.M. Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways. J. Alzheimers Dis. 2008, 13, 111–122. [Google Scholar] [PubMed]
  262. Dolga, A.M.; Granic, I.; Nijholt, I.M.; Nyakas, C.; van der Zee, E.A.; Luiten, P.G.M.; Eisel, U.L.M. Pretreatment with lovastatin prevents N-methyl-D-aspartate-induced neurodegeneration in the magnocellular nucleus basalis and behavioral dysfunction. J. Alzheimers Dis. 2009, 17, 327–336. [Google Scholar] [PubMed]
Back to TopTop