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Review

Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire!

UMR CNRS 5287 Aquitaine Institute for Integrative and Cognitive Neuroscience, University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France
Pharmaceuticals 2022, 15(2), 140; https://doi.org/10.3390/ph15020140
Submission received: 5 January 2022 / Revised: 23 January 2022 / Accepted: 24 January 2022 / Published: 25 January 2022
(This article belongs to the Special Issue Cerebral Production and Action of Pro-inflammatory Cytokines)

Abstract

:
In spite of the brain-protecting tissues of the skull, meninges, and blood-brain barrier, some forms of injury to or infection of the CNS can give rise to cerebral cytokine production and action and result in drastic changes in brain function and behavior. Interestingly, peripheral infection-induced systemic inflammation can also be accompanied by increased cerebral cytokine production. Furthermore, it has been recently proposed that some forms of psychological stress may have similar CNS effects. Different conditions of cerebral cytokine production and action will be reviewed here against the background of neuroinflammation. Within this context, it is important to both deepen our understanding along already taken paths as well as to explore new ways in which neural functioning can be modified by cytokines. This, in turn, should enable us to put forward different modes of cerebral cytokine production and action in relation to distinct forms of neuroinflammation.

1. Introduction

The brain is one of the bodily organs that is peculiar when it comes to immune responses to injury and infection. First of all, in many animal species, the brain is relatively protected from penetrating injury by the skull bone and the fibrous membranes of meninges surrounding it [1]. Although the concentration of nervous tissue in the head region of animals (cephalization) is evolutionarily ancient, the appearance of an ossified cavity containing the brain is more recent [2]. Indeed, for much of evolutionary history, the brain was protected by an exoskeleton. However, ever since the appearance of a skull bone, a certain correspondence in changes affecting the brain and those of the skull can be observed in the evolution and development of species [3,4]. This can be explained by positing that the skull also enables new feeding and sensory modalities besides providing protection of the brain [4].
Second, the so-called blood-brain barrier (BBB), formed by tight junction molecular bridges between, little fluid and particle uptake by, and low cellular passage of brain endothelial cells limits the entry of many infectious microorganisms into the central nervous system of many vertebrates [5,6]. Interestingly, BBB properties can also be found in some insects, including Drosophilia, but are then related to the structural organization of glial cells [7,8]. Furthermore, these glial cells express junction molecules and chemoprotective xenobiotic-excluding transporters, in addition to having the capacity to promote immune cell infiltration [9,10,11,12,13]. BBB properties therefore seem conserved between invertebrates and vertebrates by the expression of similar molecules, albeit in different brain cells, and may have been favored during evolution because they allowed for a more stable ionic and chemical extracellular brain environment [7].

1.1. Brain Cytokine Production and Action in Neurological Conditions: Immune Privilege Transformed

Nevertheless, and in spite of these brain-protecting tissues, some forms of head injury or infectious microorganisms can result in drastic changes in brain function and behavior as some historical examples of construction site accidents [14] and boxing- and football-related injuries [15,16], as well as the sequelae of some infectious diseases [17,18,19,20,21] illustrate. Notably, some of the infectious microorganisms that induce neurological symptoms in their hosts are capable of crossing the BBB by interacting with some of the molecules these interfaces express or by infecting immune cells that cross them [5,22,23,24]. Furthermore, brain cells, and in particular glial cells, have long been known to be capable of producing the pro-inflammatory cytokine interleukin-1 (IL-1) in response to administration of bacterial lipopolysaccharide (LPS) or local injury [25,26,27]. Interestingly, while introduction of bacterial fragments in the skin gives rise to full-blown inflammatory responses, including immune cell infiltration and the mutually-reinforcing production of the pro-inflammatory cytokines IL-1beta and tumor necrosis factor (TNF)-alpha, this is less the case in the brain parenchyma [28,29]. Thus, even though the skull, meninges, and BBB provide protection, injury to or infection of the brain tissue does occur and can lead to some inflammatory responses.
These latter observations need to be interpreted in the historical context of the idea that the brain has a privileged status regarding immunity. This idea was put forward to account for the relative lack of immune responses to tissue transplants or tumors in the CNS [30,31,32,33,34]. However, findings obtained in multiple sclerosis patients and in its animal model experimental allergic encephalomyelitis (EAE) clearly indicated that it was possible to observe immune and inflammatory responses in the brain parenchyma [35]. Moreover, from the mid-1980s onwards, the characteristics of the immune-privileged status and the conditions under which it applied became better known [36,37,38,39,40]. Thus, the observations that local injection of bacterial fragments or pro-inflammatory cytokines into the brain parenchyma gives rise to less neutrophil infiltration and cytokine induction as compared to other tissues became part of the further characterization of the immune privileged status of the CNS. It is clear, however, that its immune privileged status should not be understood as the brain being incapable of mounting immune responses [41].
While the role of brain pro-inflammatory cytokines in animal models of neurological conditions has often been guided by the hypothesis that these contribute to neuropathological processes, research findings clearly indicate that this needs to be nuanced. In the following discussion, the focus will be on IL-1, but with the idea that similar findings exist regarding TNF. Early clinical studies have shown that CSF IL-1 beta concentrations correlate with cerebral pathology in onset multiple sclerosis [42,43]. These findings have been corroborated by the detection of increased cerebral expression of IL-1beta as well as of the IL-1 receptor antagonist at sites of starting demyelination during EAE [44]. Furthermore, brain overexpression of the IL-1 receptor antagonist or IL-1 receptor deficiency reduces cerebral chemokine production, macrophage infiltration, and EAE disease severity [45,46]. More specifically, the brain endothelial selective knock-down of signaling IL-1 receptors lowers adhesion molecule expression and cerebral immune cell infiltration and clinical scores in EAE [47,48].
Already in the early 1990s, CSF IL-1beta levels were reported to be higher in Alzheimer Disease (AD) than in Multiple Sclerosis patients [49]. This, along with the increased expression of IL-1 and IL-1 converting enzyme in the temporal brain lobe of patients with AD [50,51], gave rise to the idea that pro-inflammatory cytokines play a role in AD. Interestingly, genetically-modified mice expressing the amyloid precursor protein with mutations found in familial forms of AD also show increased IL-1beta expression in glial cells in close proximity to amyloid plaques [52,53]. While the main assumption was that IL-1beta would play a detrimental role in AD, it was actually found that increased brain IL-1beta production by hippocampal IL-1beta overexpression in AD mouse models reduces amyloid plaque load, even though it increases tau pathology [54,55,56]. However, hippocampal transplantation of IL-1 receptor antagonist-expressing neural precursor cells or intracerebroventricualar administration of the IL-1 receptor antagonist has been shown to mitigate cognitive deficits in a mouse AD model and to reduce hippocampal plaque load [57]. While these findings indicate that increased brain pro-inflammatory cytokine production should not be simply assumed to play a detrimental role in the symptoms and disease processes of neurological condition, they also suggest that presumed disease processes and symptoms are not always tightly linked.

1.2. Brain Cytokine Production and Action in Physiology, Behavior, and Cognition

Interestingly, from the mid-1980s onwards, it has repeatedly been shown that the brain not only responds to local injury or infection with increased production of IL-1, but also during systemic inflammation induced by the intravenous or intraperitoneal administration of bacterial LPS [58,59,60,61,62]. Although systemic administration of bacterial LPS is often considered to be an animal model of bacterial sepsis, it is important to keep in mind that it does not mimic the hemodynamic phases observed in clinical sepsis. Importantly, cecal ligature and puncture (CLP) in rodents does reproduce clinical sepsis-associated hemodynamic phases and results in increased cerebrospinal fluid concentrations and brain expression of IL-1beta and TNF-alpha [63,64]. Finally, sepsis giving rise to fatal childhood malaria and in premature babies is also accompanied by elevated IL-1beta and TNF-alpha levels in the brain parenchyma and cerebrospinal fluid levels [65,66]. Therefore, brain pro-inflammatory cytokine production clearly not only occurs in response to local insults of central nervous tissue, but also as a result of systemic inflammation.
Although it was initially hypothesized that brain IL-1 plays a role in fever induction, it was first shown to contribute to the increased time that rodents injected with bacterial fragments spent sleeping [67,68]. Subsequently, central IL-1 action has also been reported to play a role in bacterial LPS- and CLP-induced systemic inflammation-associated fever and sickness behavior (reduced food intake and social interactions) [69,70,71,72]. Because fever and low food intake, as well as reduced activity and increased sleep, can be considered adaptive when the organism is facing a bacterial infection [73], these findings can be interpreted to suggest that IL-1 action in the brain activates specific circuits that lead to an integrated physiological and behavioral response to overcome infection. One of the outstanding questions in this respect is where in the brain IL-1 acts to bring about these physiological and behavioral changes.
Learning and memory can also be affected by the peripheral injection of bacterial LPS, but this often seems to depend on the test and experimental conditions used [74]. Although central injection of IL-1 at some doses can impair learning and memory processes [74,75], it is not established that the brain action of endogenous IL-1 mediates the effects of peripheral bacterial LPS injection on learning and memory. In fact, it has been shown that central administration of the IL-1 receptor antagonist, at a dose that attenuates peripheral bacterial LPS-induced fever, does not affect associative learning between a taste and LPS injection [76]. However, intracerebroventricular administration of IL-1 receptor antagonist has been reported to mitigate the detrimental effect of sepsis on aversive memory in the step-down inhibitory avoidance test [77]. Thus, the role of brain IL-1 in mediating bacterial infection-associated cognitive alterations remains to be further clarified.
Importantly, increased brain IL-1 production does not only occur in response to the detection of bacterial fragments. Indeed, cerebrospinal fluid concentrations of IL-1 also increase during sleep in comparison to the wake state of animals, even in the absence of exposure to microbial fragments [78,79]. Moreover, the central inhibition of IL-1 action has been shown to reduce sleep and its rebound after sleep deprivation [68,80,81]. Altogether, it thus seems that IL-1, a mediator classically associated with the immune system, plays a role in the physiological regulation of sleep in the brain.
Another potential physiological role for brain IL-1 concerns learning and memory. The first indication of this was provided by a paper showing that long-term potentiation (LTP), a mechanism thought to underlie some forms of learning, increases the expression of IL-1beta in the hippocampus and that administration of the IL-1 receptor antagonist impairs LTP maintenance [82]. Interestingly, LTP also increases hippocampal IL-6 expression, and antagonizing its action results in prolonged LTP and improved memory in a spatial alternation paradigm [83]. Beyond LTP, fear-motivated context-dependent inhibitory avoidance training has been shown to increase the expression of IL-1 alpha in the hippocampus, and local overexpression of the interleukin-1receptor antagonist has been found to improve the retention scores of this task [84]. Contextual learning of fear-conditioned freezing also increases hippocampal IL-1 beta expression with the central production of IL-1 receptor antagonist reducing freezing in this test [85]. In addition, this latter study also showed that central administration of a low dose of IL-1beta facilitates context-conditioned freezing, whereas a higher dose impairs this response [85]. Thus, there is good evidence that central IL-1 beta plays a dose-dependent role in contextual fear conditioning and hippocampal synaptic function [74,86]. Finally, other work has indicated that Morris water maze training increases the expression of the so-called anti-inflammatory cytokines IL-4 and IL-13 expression in the brain meninges and that genetic deficiency of either of these cytokines affects cognitive performance in this maze [87,88]. In summary, as for the role of brain IL-1 in systemic inflammation-associated changes in cognition, its physiological role in mediating cognition still needs to be further clarified.

1.3. ‘Psychological Stress’—Associated Cytokine Production

Although the general term ‘stress’ may be considered a vague ‘umbrella concept’, some distinctions of stress categories may prove useful. Indeed, based on the eliciting stimuli or conditions, one can distinguish between systemic, homeostatic, or physiological stressors and neurogenic, emotional, or psychological stressors. Infection-induced systemic inflammation can thus be considered a homeostatic-physiological stressor that is accompanied by pro-inflammatory cytokine production and action in the brain, at least in the experimental model consisting of peripheral LPS administration (see above).
Interestingly, a relationship between chronic emotional-psychological stress and pro-inflammatory cytokine production has also been proposed. One of the first findings indicating such a link was that of chronic caregiver stress being associated with increased expression of transcripts with response elements for NF-kappaB, a pro-inflammatory transcription factor, in circulating monocytes [89]. Many studies have subsequently looked at circulating markers and have reported increases in the plasma IL-6 of the elderly taking care of a spouse with a chronic medical condition, persons with a low socioeconomic status, victims of childhood abuse or maltreatment, and of patients with depression in comparison to respective control groups [90]. In addition, studies on animals indicated that chronic unpredictable mild stress increases serum IL-6, IL-1beta, and TNF-alpha [91], while repeated social defeat stress results in higher circulating IL-6 concentrations [92,93]. Interestingly, chronic social defeat stress has also been shown to result in increased IL-1beta synthesis in the brain [94]. While it seems clear that some stressful situations can give rise to increased cytokine production, including in the brain, the extent to which some of these stressors can be considered as purely psychological is, at present, unclear.

2. Context-Dependent Neuroinflammation and Brain Cytokine Production

Over the past four decades, it has clearly been shown that inflammatory and immune responses can occur in the brain, but also that these may be different from peripheral tissues and thus confer an immune-privileged status to the brain. As mentioned above, in response to injection of the same amount of bacterial lipopolysaccharide (LPS) fragments, the skin displays full-blown local inflammatory responses, whereas the parenchyma of the central nervous system shows delayed cellular infiltration with minimal recruitment of neutrophils [28]. However, the brain meninges, circumventricular organs, and choroid plexus display LPS-induced responses that resemble those observed in the skin [28]. Yet, after severe CNS injuries, such as stroke, the brain parenchyma can also show inflammatory responses that are reminiscent of the hallmarks of peripheral inflammation. Such responses have historically been named neuroinflammation [95]. Thus, it has been proposed that neuroinflammation refers to four signs, namely increased cytokine production, activation of microglia, peripheral immune cell recruitment, and local tissue damage [95]. However, over the years, the phenomena for which this term has been used go well beyond central nervous tissue responses to severe injuries. Indeed, the term neuroinflammation has regularly been employed after the detection of one single hallmark in a wide variety of physiological and psychological stressors [95,96,97].
As pointed out above, systemic inflammation induced by peripheral administration of bacterial LPS, as well as in animal models of sepsis, are accompanied by pro-inflammatory cytokines production, in particular at the blood-brain interfaces of the meninges, circumventricular organs, and choroid plexus. Moreover, both the peripheral administration of bacterial LPS and experimental sepsis models result in morphological signs of microglial activation [98,99,100]. Furthermore, both procedures induce immune cell infiltration of the brain [101,102,103,104,105,106]. Finally, regarding cerebral tissue damage, both BBB breakdown and neuronal death have been studied. While leakage of circulating molecules into the brain parenchyma after systemic injection of bacterial LPS or induction of sepsis has been repeatedly reported [107,108], it is important to bear in mind that BBB breakdown does not seem to be necessary for signs of sickness or encephalopathy [109,110,111,112]. While clinical septic shock, experimental sepsis, and the systemic administration of high doses of bacterial LPS can all lead to signs of neuronal apoptosis [113,114,115], this is not necessarily the case for moderate doses of LPS administered in adult animals [116]. Taken together, these findings clearly indicate that systemic inflammation during bacterial sepsis or induced by high doses of bacterial LPS can result in bona fide neuroinflammation.
Regarding the effects of psychological stress, it has already been mentioned above that chronic social defeat increases brain IL-1beta synthesis. As for glial activation, there is evidence that fear conditioning, chronic foot shock, restraint, and social defeat in adult rodents lead to microglial activity in the brain based on immunohistochemcial staining of the microglial specific marker ionized calcium binding adaptor molecule 1 (Iba-1) [117,118]. In addition to microglial activation, chronic social defeat also enhances recruitment of mononuclear immune cells to the brain perivascular spaces [119,120] and results in local breakdown of the BBB [121]. Altogether, the available evidence suggests that features of neuroinflammation, including increased pro-inflammatory CNS cytokine expression, glial activation, brain recruitment of immune cells, and breakdown of the BBB, are associated with some stress conditions in rodents, in particular with chronic social defeat. It remains to be seen, however, if neuroinflammation occurs more generally in stressful conditions beyond that induced by chronic social defeat.
In spite of the conclusion that neuroinflammation occurs during severe sepsis-like systemic inflammation and some experimental stressful conditions, it is important to keep in mind that it is based on the consideration of a whole corpus of published articles and that there are important differences in the type of neuroinflammation between these conditions. This is especially important in a context where some individual articles make conclusions regarding the occurrence of neuroinflammation when addressing only one feature, for example microglial activation, in a particular condition [97,117].

3. Novel Insights into Brain Cytokine Production and Action

In what follows, different aspects of cerebral cytokine production and action, as recently reported in Pharmaceuticals, will be discussed. If, in the previous sections, the focus was mainly focused on IL-1 to more clearly set the different contextual scenes, these articles also assess many other cytokines. The discussion will start within the context of neurology and progressively move to physiology and behavior before touching on more psychiatric aspects.
As alluded to above, MS and its animal model EAE have been studied extensively with regard to the role of cytokines and neuroinflammation. Although intercellular communication via cytokine release into the extracellular cerebral environment has been mostly addressed, there are other ways in which different brain cell types can interact. For example, gap junctions, made up of connexin molecules, connect different glial cell types and enable the exchange of small molecules. Interestingly, the expression of connexins is increased in MS [122], and mutations in connexin molecules are associated with myelin-related disorders, such as X-linked Charcot–Marie–Tooth disease [123]. While this suggests that connexins could play a role in MS pathophysiology, mice that are genetically-deficient in individual connexins do not spontaneously show signs of demyelination [124,125]. However, and as shown previously by the group of Kleopa, these mice are more susceptible to EAE with higher clinical scores and more severe neuroinflammation and demyelination [126]. In a follow-up study, published in Pharmaceuticals, this group studied CNS blood-spinal cord interfaces; immune cell infiltration; and the expression of certain adhesion molecules, chemokines, and cytokines at different time points prior to and after EAE onset in connexin-deficient mice. It was thus confirmed that mice deficient in connexin-47, expressed mainly by oligodendrocytes, have a faster-appearing and more severe disease with higher immune cell infiltration, along with lower blood spinal cord barrier-associated tight junction molecule expression already before disease onset [127]. Interestingly, none of these early phenomena were found to be accompanied by a significant increase in the CNS expression of the adhesion molecules, chemokines, and cytokines considered, even though changes were observed later during the disease cause [127]. These findings strongly encourage researchers to address factors other than the usual suspects in the context of emerging neuroinflammation.
In the preceding sections, it was pointed out how cerebral cytokine production and neuroinflammation not only occur in response to local insult of the CNS, as in MS or EAE, but also during systemic inflammation secondary to peripheral infection. However, almost all the findings indicating brain cytokine production and other signs of neuroinflammation during system inflammation have been obtained in animal models of bacterial infection. It is thus important to establish to what extent these phenomena also occur during viral infections. As indicated by Bohmwald et al. in Pharmaceuticals, “increased levels of pro-inflammatory molecules, such as IL-1beta, IL-6, and TNF-alpha, have been detected in the CSF of patients showing neurological alterations due to influenza virus infection” [128] (p. 4). Moreover, these clinical findings are corroborated by experimental studies showing increased cerebral expression of pro-inflammatory cytokines inoculated peripherally with the influenza virus [128]. Therefore, while it seems clear that pro-inflammatory cytokines are being produced in the brain in response to a peripheral influenza infection, the sites of the action and the role(s) of these cytokines in mediating viral infection-associated symptoms remain to be clarified.
In an effort to deepen our understanding of the neuroinflammatory mechanisms relevant to sepsis-associated encephalopathy, Moraes et al. offer a review, published in Pharmaceuticals, focusing on the activation of microglial cells by danger-associated molecular patterns and pathogen-associated molecular patterns and their consequences in the context of brain dysfunction during sepsis. These authors relate findings of several postmortem studies showing increased cerebral expression of CD68, which can be taken as an indicator of microglial activation, in patients who had succumbed to sepsis [129,130,131]. Furthermore, Moraes et al. hypothesize that “IL-1beta derived from activated microglia is responsible for the synaptic deficits observed in sepsis” [132] (p. 12).
Obviously, bacterial sepsis can induce the production of many cytokines, including in the brain. In an animal model that attempts to mimic the massive release of bacterial LPS sometimes observed in clinical sepsis [133], Peek et al., in their article published in Pharmaceuticals, focused on the High Mobility Group Box-1 Protein (HMGB-1), a nuclear DNA-binding protein that alters the structure of chromatin, but which can serve as a danger-associated molecular pattern or alarmin and mimic pro-inflammatory cytokine activity when present in the extracellular space [134]. These authors relate studies showing that circulating concentrations of HMGB-1 are increased during severe clinical sepsis and septic shock [135] and several hours after the peripheral administration of high doses of LPS to rodents [136]. Interestingly, oxidative stress favors the formation of disulfide HMGB-1, which can, just like bacterial LPS, activate the toll-like receptor 4 (TLR4) [134]. Given that TLR4 is preferentially expressed in brain circumventricular organs lacking a functional BBB [137], Peek et al. set out to study the effects of disulfide-HMGB-1 on the neuro-glial cell cultures of the area postrema, the brainstem circumventricular organ, as well as the effects of prior bacterial LPS-induced inflammation on the response of area postrema cells to HMGB-1. While they confirmed that peripheral administration of LPS leads to a sustained increase in circulating HMGB-1, they also provided in vivo evidence of LPS-induced nucleus-to-cytoplasm translocation of HMGBI in the hypothalamus and area postrema, which can be interpreted to represent a step in HMGB-1 release into the extracellular environment [138]. This latter effect could be reproduced in vitro by exposing area postrema cultures to LPS. Mimicking HMGB-1 release by exposing area postrema cultures to disulfide HMGB-1 resulted in increased nuclear factor-kappaB staining in cell nuclei, indicating the activation of a pro-inflammatory intracellular signaling cascade and IL-6 release [138]. Finally, Peek et al. obtained evidence that prior LPS exposure primes area postrema cultures’ responsiveness to subsequent HGMB1 [138]. Thus, HGMB1 can be hypothesized to play a role in the sustained effects of bacterial LPS on the brain.
The contribution of Kvivik et al. in Pharmaceuticals on the detection of HMGB-1 in biological fluids is relevant for that of many classic cytokines as proteins with molecular weights between 6 and 70 kDa [139]. These authors hypothesize that HMGB-1 could play an important role in mediating sickness behavior, but they were confronted with the difficulties of current available methods, such as autoantibodies or plasma proteins interfering with the detection of HMGB-1 by enzyme-linked immunosorbent assay. They, therefore, set out to develop an antibody-free liquid chromatography coupled with a tandem mass spectrometry-based detection method for HMGB-1. In particular, Kvivik et al. showed that, notwithstanding suboptimal recovery, the method developed enabled “the identification of several unique HMGB-1 peptides” [140] (p. 12). This accomplishment, in turn, has the potential to allow for “the measurement of different redox variants” in the future [140] (p. 12).
In the context of the study of sickness behavior, Chaskiel et al. tested the role of IL-1 receptor-expressing cerebral perivascular macrophages in mediating reduced food intake and carried out exploration after central systemic administration of IL-1beta. The authors showed previously that the peripheral IL-1beta-induced reduction of food intake is, in part, mediated by IL-1 receptors in the arcuate hypothalamus [141] and wondered if another part could be played by brain perivascular macrophages, also known to express IL-1 receptors [142]. To test the role of IL-1 receptor brain macrophages, the work of Chaskiel et al., published in Pharmaceuticals, employed IL-1 coupled to the ribosome toxin, saporin, and administered this conjugate into forebrain ventricles, from where molecules spread preferentially through perivascular spaces. This intervention effectively reduced the number of CD163-positive perivascular macrophages in a forebrain circumventricular organ as well as along vessels forming a functional BBB, but it did not affect the reduction of food intake after subsequent IL-1beta administration [143]. Therefore, while these findings clearly indicate that brain perivascular macrophages do not mediate IL-1-induced sickness behavior in rats, it remains possible that these cells play an important role in bringing about sickness behavior as cerebral sources of IL-1 beta production in response to circulating bacterial fragments.
Finally, two articles in Pharmaceuticals address the cerebral actions of cytokines in the context of mental disorders. The first, by Ivanovska et al., is a review focused on the chemoattractant cytokine eosinophil chemotactic protein CCL-11, also called eotaxin, which binds to CCR3 [144]. Of particular interest to the topic of cerebral cytokine production action is the finding that helminth infection can result in increased CSF CCL-11/eotaxin concentrations [145,146]. Other interesting features of this cytokine are that blood CCL-11/eotaxin concentrations increase with age [147] and that circulating CCL-11/eotaxin is likely to be transported into the CNS and accumulate there [148]. After a review of the relevant literature, Ivanovska et al. conclude that: “Plasma levels of CCL-11 are increased not only in schizophrenia and age-related cognitive impairments, but also in some patients with mood disorders” [149] (p. 10). Although the conditions in which circulating CCL-11/eotaxin is reported to be increased seem, at first sight, to be very different, they may have much in common “accelerated aging” [150] (p. 1). Scheiber et al. address similar questions by measuring plasma and CSF cytokines and the surface antigen expression of circulating immune cells. Their results, to be reported in Pharmaceuticals, show that CSF IL-8 concentrations were higher than in the blood of patients with affective spectrum disorder or schizophrenic spectrum disorder. In contrast, plasma IL-1 beta concentrations were found to be higher than those in CSF for patients with schizophrenic spectrum disorder (Scheiber et al., Pharmaceuticals, under review). In light of these findings suggesting increased IL-8 brain production in affective spectrum and schizophrenic spectrum disorders and given the neutrophil chemoattractant role of this cytokine [151], one would like to see future studies addressing CSF neutrophil counts in these mental disorders. If this were to be true, then the case for some form of neuroinflammation accompanying certain mental disorders would be considerably strengthened.

4. Conclusions

The aim of this review, as part of the Special Issue of Pharmaceuticals on “cerebral production and action of cytokines”, was to better understand cytokine production and action in the brain beyond their involvement in local immune responses to an insult or infection of the CNS. One domain in which research into brain cytokine production and action has been particularly active over the past decades is that searching to explain the occurrence of non-specific disease symptoms involving CNS-regulated physiology and behavior, such as fever, increased sleep, and reduced food intake, after the systemic detection of bacterial fragments. An important outstanding question in this respect is how to distinguish sickness physiology and behavior and the underlying neuroimmune communication pathways from the neuroinflammatory processes involved in sepsis-associated encephalopathy. Another domain of research addressing the role of brain cytokine production and action concerns the regulation of some important functions, including sleep and cognition. While the majority of the work on brain cytokine production and action has historically concerned a couple of pro-inflammatory cytokines, such as IL-1, it is important to realize that cytokines comprise many different biologically active molecules and include interferons, interleukins, and chemokines, but also, for example, adipokines. Thus, several new perspectives have arisen regarding cytokine brain production and action that surpass classic neuroimmunology and neuroinflammation and seem closer in spirit to integrative physiology and behavior. These new perspectives can, in the long run, be expected to give rise to new therapeutic avenues.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Derk, J.; Jones, H.E.; Como, C.; Pawlikowski, B.; Siegenthaler, J.A. Living on the edge of the cns: Meninges cell diversity in health and disease. Front. Cell Neurosci. 2021, 15, 703944. [Google Scholar] [CrossRef] [PubMed]
  2. Janvier, P. The brain in the early fossil jawless vertebrates: Evolutionary information from an empty nutshell. Brain Res. Bull. 2008, 75, 314–318. [Google Scholar] [CrossRef] [PubMed]
  3. Richtsmeier, J.T.; Flaherty, K. Hand in glove: Brain and skull in development and dysmorphogenesis. Acta Neuropathol. 2013, 125, 469–489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. White, H.E.; Goswami, A.; Tucker, A.S. The intertwined evolution and development of sutures and cranial morphology. Front. Cell Dev. Biol. 2021, 9, 653579. [Google Scholar] [CrossRef]
  5. van Sorge, N.M.; Doran, K.S. Defense at the border: The blood-brain barrier versus bacterial foreigners. Future Microbiol. 2012, 7, 383–394. [Google Scholar] [CrossRef] [Green Version]
  6. Sharif, Y.; Jumah, F.; Coplan, L.; Krosser, A.; Sharif, K.; Tubbs, R.S. Blood brain barrier: A review of its anatomy and physiology in health and disease. Clin. Anat. 2018, 31, 812–823. [Google Scholar] [CrossRef]
  7. Abbott, N.J. Dynamics of cns barriers: Evolution, differentiation, and modulation. Cell Mol. Neurobiol. 2005, 25, 5–23. [Google Scholar] [CrossRef]
  8. Daneman, R.; Barres, B.A. The blood-brain barrier--lessons from moody flies. Cell 2005, 123, 9–12. [Google Scholar] [CrossRef] [Green Version]
  9. Wu, V.M.; Schulte, J.; Hirschi, A.; Tepass, U.; Beitel, G.J. Sinuous is a drosophila claudin required for septate junction organization and epithelial tube size control. J. Cell Biol. 2004, 164, 313–323. [Google Scholar] [CrossRef]
  10. Mayer, F.; Mayer, N.; Chinn, L.; Pinsonneault, R.L.; Kroetz, D.; Bainton, R.J. Evolutionary conservation of vertebrate blood-brain barrier chemoprotective mechanisms in drosophila. J. Neurosci. 2009, 29, 3538–3550. [Google Scholar] [CrossRef]
  11. DeSalvo, M.K.; Hindle, S.J.; Rusan, Z.M.; Orng, S.; Eddison, M.; Halliwill, K.; Bainton, R.J. The drosophila surface glia transcriptome: Evolutionary conserved blood-brain barrier processes. Front. Neurosci. 2014, 8, 346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Kubick, N.; Klimovich, P.; Bienkowska, I.; Poznanski, P.; Lazarczyk, M.; Sacharczuk, M.; Mickael, M.E. Investigation of evolutionary history and origin of the tre1 family suggests a role in regulating hemocytes cells infiltration of the blood-brain barrier. Insects 2021, 12, 882. [Google Scholar] [CrossRef] [PubMed]
  13. Mickael, M.E.; Kubick, N.; Klimovich, P.; Flournoy, P.H.; Bienkowska, I.; Sacharczuk, M. Paracellular and transcellular leukocytes diapedesis are divergent but interconnected evolutionary events. Genes 2021, 12, 254. [Google Scholar] [CrossRef] [PubMed]
  14. Macmillan, M. Restoring phineas gage: A 150th retrospective. J. Hist. Neurosci. 2000, 9, 46–66. [Google Scholar] [CrossRef]
  15. Montenigro, P.H.; Corp, D.T.; Stein, T.D.; Cantu, R.C.; Stern, R.A. Chronic traumatic encephalopathy: Historical origins and current perspective. Annu. Rev. Clin. Psychol. 2015, 11, 309–330. [Google Scholar] [CrossRef]
  16. Verduyn, C.; Bjerke, M.; Duerinck, J.; Engelborghs, S.; Peers, K.; Versijpt, J.; D’Haeseleer, M. Csf and blood neurofilament levels in athletes participating in physical contact sports: A systematic review. Neurology 2021, 96, 705–715. [Google Scholar] [CrossRef]
  17. Ghanem, K.G. Review: Neurosyphilis: A historical perspective and review. CNS Neurosci. Ther. 2010, 16, e157–e168. [Google Scholar] [CrossRef]
  18. Abio, A.; Neal, K.R.; Beck, C.R. An epidemiological review of changes in meningococcal biology during the last 100 years. Pathog. Glob. Health 2013, 107, 373–380. [Google Scholar] [CrossRef] [Green Version]
  19. Mogk, S.; Bosselmann, C.M.; Mudogo, C.N.; Stein, J.; Wolburg, H.; Duszenko, M. African trypanosomes and brain infection—the unsolved question. Biol. Rev. Camb. Philos. Soc. 2017, 92, 1675–1687. [Google Scholar] [CrossRef]
  20. Bond, M.; Bechter, K.; Muller, N.; Tebartz van Elst, L.; Meier, U.C. A role for pathogen risk factors and autoimmunity in encephalitis lethargica? Prog. Neuropsychopharmacol. Biol. Psychiatry 2021, 109, 110276. [Google Scholar] [CrossRef]
  21. Stefano, G.B. Historical insight into infections and disorders associated with neurological and psychiatric sequelae similar to long COVID. Med. Sci. Monit. 2021, 27, e931447. [Google Scholar] [CrossRef] [PubMed]
  22. Nassif, X.; Bourdoulous, S.; Eugene, E.; Couraud, P.O. How do extracellular pathogens cross the blood-brain barrier? Trends Microbiol. 2002, 10, 227–232. [Google Scholar] [CrossRef]
  23. Kim, K.S. Mechanisms of microbial traversal of the blood-brain barrier. Nat. Rev. Microbiol. 2008, 6, 625–634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Coureuil, M.; Lecuyer, H.; Bourdoulous, S.; Nassif, X. A journey into the brain: Insight into how bacterial pathogens cross blood-brain barriers. Nat. Rev. Microbiol. 2017, 15, 149–159. [Google Scholar] [CrossRef] [PubMed]
  25. Fontana, A.; Kristensen, F.; Dubs, R.; Gemsa, D.; Weber, E. Production of prostaglandin e and an interleukin-1 like factor by cultured astrocytes and c6 glioma cells. J. Immunol. 1982, 129, 2413–2419. [Google Scholar] [PubMed]
  26. Coceani, F.; Lees, J.; Dinarello, C.A. Occurrence of interleukin-1 in cerebrospinal fluid of the conscious cat. Brain Res. 1988, 446, 245–250. [Google Scholar] [CrossRef]
  27. Hetier, E.; Ayala, J.; Denefle, P.; Bousseau, A.; Rouget, P.; Mallat, M.; Prochiantz, A. Brain macrophages synthesize interleukin-1 and interleukin-1 mrnas in vitro. J. Neurosci. Res. 1988, 21, 391–397. [Google Scholar] [CrossRef]
  28. Andersson, P.B.; Perry, V.H.; Gordon, S. The acute inflammatory response to lipopolysaccharide in cns parenchyma differs from that in other body tissues. Neuroscience 1992, 48, 169–186. [Google Scholar] [CrossRef]
  29. Blond, D.; Campbell, S.J.; Butchart, A.G.; Perry, V.H.; Anthony, D.C. Differential induction of interleukin-1beta and tumour necrosis factor-alpha may account for specific patterns of leukocyte recruitment in the brain. Brain Res. 2002, 958, 89–99. [Google Scholar] [CrossRef]
  30. Murphy, J.B.; Sturm, E. Conditions determining the transplantability of tissues in the brain. J. Exp. Med. 1923, 38, 183–197. [Google Scholar] [CrossRef] [Green Version]
  31. Medawar, P.B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 1948, 29, 58–69. [Google Scholar] [PubMed]
  32. Rambo, O.N., Jr.; Fuson, R.; Hattori, M.; Eichwald, E.J. Immune phenomena elicited by transplanted tumors. I. The participation of the eye and the brain. Cancer Res. 1954, 14, 169–172. [Google Scholar] [PubMed]
  33. Morantz, R.A.; Shain, W.; Cravioto, H. Immune surveillance and tumors of the nervous system. J. Neurosurg. 1978, 49, 84–92. [Google Scholar] [CrossRef] [PubMed]
  34. Head, J.R.; Griffin, W.S. Functional capacity of solid tissue transplants in the brain: Evidence for immunological privilege. Proc. R Soc. Lond. B Biol. Sci. 1985, 224, 375–387. [Google Scholar]
  35. Roboz-Einstein, E. Allergic encephalomyelitis as an experimental model for multiple sclerosis. Calif. Med. 1959, 91, 204–206. [Google Scholar]
  36. Aarli, J.A. The immune system and the nervous system. J. Neurol. 1983, 229, 137–154. [Google Scholar] [CrossRef]
  37. Hickey, W.F.; Kimura, H. Graft-vs.-host disease elicits expression of class i and class ii histocompatibility antigens and the presence of scattered t lymphocytes in rat central nervous system. Proc. Natl. Acad. Sci. USA 1987, 84, 2082–2086. [Google Scholar] [CrossRef] [Green Version]
  38. Nicholas, M.K.; Antel, J.P.; Stefansson, K.; Arnason, B.G. Rejection of fetal neocortical neural transplants by h-2 incompatible mice. J. Immunol. 1987, 139, 2275–2283. [Google Scholar]
  39. Streit, W.J.; Graeber, M.B.; Kreutzberg, G.W. Functional plasticity of microglia: A review. Glia 1988, 1, 301–307. [Google Scholar] [CrossRef]
  40. Pollack, I.F.; Lund, R.D. The blood-brain barrier protects foreign antigens in the brain from immune attack. Exp. Neurol. 1990, 108, 114–121. [Google Scholar] [CrossRef]
  41. Galea, I.; Bechmann, I.; Perry, V.H. What is immune privilege (not)? Trends Immunol. 2007, 28, 12–18. [Google Scholar] [CrossRef] [PubMed]
  42. Rovaris, M.; Barnes, D.; Woodrofe, N.; du Boulay, G.H.; Thorpe, J.W.; Thompson, A.J.; McDonald, W.I.; Miller, D.H. Patterns of disease activity in multiple sclerosis patients: A study with quantitative gadolinium-enhanced brain mri and cytokine measurement in different clinical subgroups. J. Neurol. 1996, 243, 536–542. [Google Scholar] [CrossRef] [PubMed]
  43. Seppi, D.; Puthenparampil, M.; Federle, L.; Ruggero, S.; Toffanin, E.; Rinaldi, F.; Perini, P.; Gallo, P. Cerebrospinal fluid il-1beta correlates with cortical pathology load in multiple sclerosis at clinical onset. J. Neuroimmunol. 2014, 270, 56–60. [Google Scholar] [CrossRef] [PubMed]
  44. Prins, M.; Eriksson, C.; Wierinckx, A.; Bol, J.G.; Binnekade, R.; Tilders, F.J.; Van Dam, A.M. Interleukin-1beta and interleukin-1 receptor antagonist appear in grey matter additionally to white matter lesions during experimental multiple sclerosis. PLoS ONE 2013, 8, e83835. [Google Scholar] [CrossRef]
  45. Furlan, R.; Bergami, A.; Brambilla, E.; Butti, E.; De Simoni, M.G.; Campagnoli, M.; Marconi, P.; Comi, G.; Martino, G. Hsv-1-mediated il-1 receptor antagonist gene therapy ameliorates mog(35-55)-induced experimental autoimmune encephalomyelitis in c57bl/6 mice. Gene Ther. 2007, 14, 93–98. [Google Scholar] [CrossRef]
  46. McCandless, E.E.; Budde, M.; Lees, J.R.; Dorsey, D.; Lyng, E.; Klein, R.S. Il-1r signaling within the central nervous system regulates cxcl12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J. Immunol. 2009, 183, 613–620. [Google Scholar] [CrossRef] [Green Version]
  47. Li, Q.; Powell, N.; Zhang, H.; Belevych, N.; Ching, S.; Chen, Q.; Sheridan, J.; Whitacre, C.; Quan, N. Endothelial il-1r1 is a critical mediator of eae pathogenesis. Brain Behav. Immun. 2011, 25, 160–167. [Google Scholar] [CrossRef] [Green Version]
  48. Hauptmann, J.; Johann, L.; Marini, F.; Kitic, M.; Colombo, E.; Mufazalov, I.A.; Krueger, M.; Karram, K.; Moos, S.; Wanke, F.; et al. Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier. Acta Neuropathol. 2020, 140, 549–567. [Google Scholar] [CrossRef]
  49. Cacabelos, R.; Barquero, M.; García, P.; Alvarez, X.A.; Varela de Seijas, E. Cerebrospinal fluid interleukin-1 beta (il-1 beta) in alzheimer’s disease and neurological disorders. Methods Find. Exp. Clin. Pharm. 1991, 13, 455–458. [Google Scholar]
  50. Griffin, W.S.; Stanley, L.C.; Ling, C.; White, L.; MacLeod, V.; Perrot, L.J.; White, C.L.; Araoz, C. Brain interleukin 1 and s-100 immunoreactivity are elevated in down syndrome and alzheimer disease. Proc. Natl. Acad. Sci. USA 1989, 86, 7611–7615. [Google Scholar] [CrossRef] [Green Version]
  51. Zhu, S.G.; Sheng, J.G.; Jones, R.A.; Brewer, M.M.; Zhou, X.Q.; Mrak, R.E.; Griffin, W.S. Increased interleukin-1beta converting enzyme expression and activity in alzheimer disease. J. Neuropathol. Exp. Neurol. 1999, 58, 582–587. [Google Scholar] [CrossRef] [PubMed]
  52. Mehlhorn, G.; Hollborn, M.; Schliebs, R. Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic tg2576 mice with alzheimer pathology. Int. J. Dev. Neurosci. 2000, 18, 423–431. [Google Scholar] [CrossRef]
  53. Apelt, J.; Schliebs, R. Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic tg2576 mice with alzheimer plaque pathology. Brain Res. 2001, 894, 21–30. [Google Scholar] [CrossRef]
  54. Shaftel, S.S.; Kyrkanides, S.; Olschowka, J.A.; Miller, J.N.; Johnson, R.E.; O’Banion, M.K. Sustained hippocampal il-1 beta overexpression mediates chronic neuroinflammation and ameliorates alzheimer plaque pathology. J. Clin. Investig. 2007, 117, 1595–1604. [Google Scholar] [CrossRef]
  55. Matousek, S.B.; Ghosh, S.; Shaftel, S.S.; Kyrkanides, S.; Olschowka, J.A.; O’Banion, M.K. Chronic il-1beta-mediated neuroinflammation mitigates amyloid pathology in a mouse model of alzheimer’s disease without inducing overt neurodegeneration. J. Neuroimmune Pharmacol. 2012, 7, 156–164. [Google Scholar] [CrossRef]
  56. Ghosh, S.; Wu, M.D.; Shaftel, S.S.; Kyrkanides, S.; LaFerla, F.M.; Olschowka, J.A.; O’Banion, M.K. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an alzheimer’s mouse model. J. Neurosci. 2013, 33, 5053–5064. [Google Scholar] [CrossRef]
  57. Ben-Menachem-Zidon, O.; Ben-Menahem, Y.; Ben-Hur, T.; Yirmiya, R. Intra-hippocampal transplantation of neural precursor cells with transgenic over-expression of il-1 receptor antagonist rescues memory and neurogenesis impairments in an alzheimer’s disease model. Neuropsychopharmacology 2014, 39, 401–414. [Google Scholar] [CrossRef] [Green Version]
  58. Fontana, A.; Weber, E.; Dayer, J.M. Synthesis of interleukin 1/endogenous pyrogen in the brain of endotoxin-treated mice: A step in fever induction? J. Immunol. 1984, 133, 1696–1698. [Google Scholar]
  59. Hooghe-Peters, E.; Velkeniers, B.; Vanhaelst, L.; Hooghe, R. Interleukin-1, interleukin-6: Messengers in the neuroendocrine immune system? Pathol. Res. Pract. 1991, 187, 622–625. [Google Scholar] [CrossRef]
  60. van Dam, A.M.; Brouns, M.; Louisse, S.; Berkenbosch, F. Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: A pathway for the induction of non-specific symptoms of sickness? Brain Res. 1992, 588, 291–296. [Google Scholar] [CrossRef]
  61. Quan, N.; Sundar, S.K.; Weiss, J.M. Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J. Neuroimmunol. 1994, 49, 125–134. [Google Scholar] [CrossRef]
  62. Konsman, J.P.; Kelley, K.; Dantzer, R. Temporal and spatial relationships between lipopolysaccharide-induced expression of fos, interleukin-1beta and inducible nitric oxide synthase in rat brain. Neuroscience 1999, 89, 535–548. [Google Scholar] [CrossRef]
  63. Meyer, T.A.; Wang, J.J.; Tiao, G.M.; Ogle, C.K.; Fischer, J.E.; Hasselgren, P.O. Sepsis and endotoxaemia in mice stimulate the expression of interleukin-i and interleukin-6 in the central nervous system. Clin. Sci. 1997, 92, 519–525. [Google Scholar] [CrossRef] [PubMed]
  64. Biff, D.; Petronilho, F.; Constantino, L.; Vuolo, F.; Zamora-Berridi, G.J.; Dall’Igna, D.M.; Comim, C.M.; Quevedo, J.; Kapczinski, F.; Dal-Pizzol, F. Correlation of acute phase inflammatory and oxidative markers with long-term cognitive impairment in sepsis survivors rats. Shock 2013, 40, 45–48. [Google Scholar] [CrossRef] [PubMed]
  65. Armah, H.; Dodoo, A.K.; Wiredu, E.K.; Stiles, J.K.; Adjei, A.A.; Gyasi, R.K.; Tettey, Y. High-level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria. Ann. Trop. Med. Parasitol. 2005, 99, 629–647. [Google Scholar] [CrossRef]
  66. Basu, S.; Agarwal, P.; Anupurba, S.; Shukla, R.; Kumar, A. Elevated plasma and cerebrospinal fluid interleukin-1 beta and tumor necrosis factor-alpha concentration and combined outcome of death or abnormal neuroimaging in preterm neonates with early-onset clinical sepsis. J. Perinatol. 2015, 35, 855–861. [Google Scholar] [CrossRef]
  67. Imeri, L.; Opp, M.R.; Krueger, J.M. An il-1 receptor and an il-1 receptor antagonist attenuate muramyl dipeptide- and il-1-induced sleep and fever. Am. J. Physiol. 1993, 265, R907–R913. [Google Scholar] [CrossRef]
  68. Takahashi, S.; Kapás, L.; Fang, J.; Seyer, J.M.; Wang, Y.; Krueger, J.M. An interleukin-1 receptor fragment inhibits spontaneous sleep and muramyl dipeptide-induced sleep in rabbits. Am. J. Physiol. 1996, 271, R101–R108. [Google Scholar] [CrossRef]
  69. Luheshi, G.; Miller, A.J.; Brouwer, S.; Dascombe, M.J.; Rothwell, N.J.; Hopkins, S.J. Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat. Am. J. Physiol. 1996, 270, E91–E95. [Google Scholar] [CrossRef]
  70. Gourine, A.V.; Rudolph, K.; Tesfaigzi, J.; Kluger, M.J. Role of hypothalamic interleukin-1beta in fever induced by cecal ligation and puncture in rats. Am. J. Physiol. 1998, 275, R754–R761. [Google Scholar]
  71. Layé, S.; Gheusi, G.; Cremona, S.; Combe, C.; Kelley, K.; Dantzer, R.; Parnet, P. Endogenous brain il-1 mediates lps-induced anorexia and hypothalamic cytokine expression. Am. J. Physiol. 2000, 179, R93–R98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Konsman, J.P.; Veeneman, J.; Combe, C.; Poole, S.; Luheshi, G.N.; Dantzer, R. Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide. Eur. J. Neurosci. 2008, 28, 2499–2510. [Google Scholar] [CrossRef] [PubMed]
  73. Sylvia, K.E.; Demas, G.E. A return to wisdom: Using sickness behaviors to integrate ecological and translational research. Integr. Comp. Biol. 2017, 57, 1204–1213. [Google Scholar] [CrossRef] [PubMed]
  74. Cunningham, C.; Sanderson, D.J. Malaise in the water maze: Untangling the effects of lps and il-1beta on learning and memory. Brain Behav. Immun. 2008, 22, 1117–1127. [Google Scholar] [CrossRef] [Green Version]
  75. Lynch, M.A. Neuroinflammatory changes negatively impact on ltp: A focus on il-1beta. Brain Res. 2015, 1621, 197–204. [Google Scholar] [CrossRef]
  76. Pacheco-Lopez, G.; Niemi, M.B.; Kou, W.; Baum, S.; Hoffman, M.; Altenburger, P.; del Rey, A.; Besedovsky, H.O.; Schedlowski, M. Central blockade of il-1 does not impair taste-lps associative learning. Neuroimmunomodulation 2007, 14, 150–156. [Google Scholar] [CrossRef]
  77. Mina, F.; Comim, C.M.; Dominguini, D.; Cassol, O.J., Jr.; Dall Igna, D.M.; Ferreira, G.K.; Silva, M.C.; Galant, L.S.; Streck, E.L.; Quevedo, J.; et al. Il1-beta involvement in cognitive impairment after sepsis. Mol. Neurobiol. 2014, 49, 1069–1076. [Google Scholar] [CrossRef]
  78. Lue, F.A.; Bail, M.; Jephthah-Ochola, J.; Carayanniotis, K.; Gorczynski, R.; Moldofsky, H. Sleep and cerebrospinal fluid interleukin-1-like activity in the cat. Int. J. Neurosci. 1988, 42, 179–183. [Google Scholar]
  79. Taishi, P.; Chen, Z.; Obál, F.E.R.E.N.C., Jr.; Hansen, M.K.; Zhang, J.; Fang, J.; Krueger, J.M. Sleep-associated changes in interleukin-1beta mrna in the brain. J. Interferon Cytokine Res. 1998, 18, 793–798. [Google Scholar] [CrossRef]
  80. Opp, M.R.; Krueger, J.M. Anti-interleukin-1 beta reduces sleep and sleep rebound after sleep deprivation in rats. Am. J. Physiol. 1994, 266, R688–R695. [Google Scholar] [CrossRef]
  81. Takahashi, S.; Fang, J.; Kapás, L.; Wang, Y.; Krueger, J.M. Inhibition of brain interleukin-1 attenuates sleep rebound after sleep deprivation in rabbits. Am. J. Physiol. 1997, 273, R677–R682. [Google Scholar] [CrossRef] [PubMed]
  82. Schneider, H.; Pitossi, F.; Balschun, D.; Wagner, A.; del Rey, A.; Besedovsky, H.O. A neuromodulatory role of interleukin-1beta in the hippocampus. Proc. Natl. Acad. Sci. USA 1998, 95, 7778–7783. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Balschun, D.; Wetzel, W.; Del Rey, A.; Pitossi, F.; Schneider, H.; Zuschratter, W.; Besedovsky, H.O. Interleukin-6: A cytokine to forget. FASEB J. 2004, 18, 1788–1790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Depino, A.M.; Alonso, M.; Ferrari, C.; del Rey, A.; Anthony, D.; Besedovsky, H.; Medina, J.H.; Pitossi, F. Learning modulation by endogenous hippocampal il-1: Blockade of endogenous il-1 facilitates memory formation. Hippocampus 2004, 14, 526–535. [Google Scholar] [CrossRef] [PubMed]
  85. Goshen, I.; Kreisel, T.; Ounallah-Saad, H.; Renbaum, P.; Zalzstein, Y.; Ben-Hur, T.; Levy-Lahad, E.; Yirmiya, R. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 2007, 32, 1106–1115. [Google Scholar] [CrossRef] [PubMed]
  86. Lynch, M.A. Interleukin-1 beta exerts a myriad of effects in the brain and in particular in the hippocampus: Analysis of some of these actions. Vitam. Horm. 2002, 64, 185–219. [Google Scholar]
  87. Derecki, N.C.; Cardani, A.N.; Yang, C.H.; Quinnies, K.M.; Crihfield, A.; Lynch, K.R.; Kipnis, J. Regulation of learning and memory by meningeal immunity: A key role for il-4. J. Exp. Med. 2010, 207, 1067–1080. [Google Scholar] [CrossRef] [Green Version]
  88. Brombacher, T.M.; Nono, J.K.; De Gouveia, K.S.; Makena, N.; Darby, M.; Womersley, J.; Tamgue, O.; Brombacher, F. Il-13-mediated regulation of learning and memory. J. Immunol. 2017, 198, 2681–2688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Miller, G.E.; Chen, E.; Sze, J.; Marin, T.; Arevalo, J.M.; Doll, R.; Ma, R.; Cole, S.W. A functional genomic fingerprint of chronic stress in humans: Blunted glucocorticoid and increased nf-kappab signaling. Biol. Psychiatry 2008, 64, 266–272. [Google Scholar] [CrossRef] [Green Version]
  90. Rohleder, N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom. Med. 2014, 76, 181–189. [Google Scholar] [CrossRef]
  91. Lopez-Lopez, A.L.; Jaime, H.B.; Escobar Villanueva, M.D.C.; Padilla, M.B.; Palacios, G.V.; Aguilar, F.J.A. Chronic unpredictable mild stress generates oxidative stress and systemic inflammation in rats. Physiol. Behav. 2016, 161, 15–23. [Google Scholar] [CrossRef] [PubMed]
  92. Hodes, G.E.; Pfau, M.L.; Leboeuf, M.; Golden, S.A.; Christoffel, D.J.; Bregman, D.; Rebusi, N.; Heshmati, M.; Aleyasin, H.; Warren, B.L.; et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl. Acad. Sci. USA 2014, 111, 16136–16141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Stewart, A.M.; Roy, S.; Wong, K.; Gaikwad, S.; Chung, K.M.; Kalueff, A.V. Cytokine and endocrine parameters in mouse chronic social defeat: Implications for translational ’cross-domain’ modeling of stress-related brain disorders. Behav. Brain Res. 2015, 276, 84–91. [Google Scholar] [CrossRef]
  94. Hueston, C.M.; Barnum, C.J.; Eberle, J.A.; Ferraioli, F.J.; Buck, H.M.; Deak, T. Stress-dependent changes in neuroinflammatory markers observed after common laboratory stressors are not seen following acute social defeat of the sprague dawley rat. Physiol. Behav. 2011, 104, 187–198. [Google Scholar] [CrossRef] [PubMed]
  95. Estes, M.L.; McAllister, A.K. Alterations in immune cells and mediators in the brain: It’s not always neuroinflammation! Brain Pathol. 2014, 24, 623–630. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Konsman, J.P. Inflammation and depression: A nervous plea for psychiatry to not become immune to interpretation. Pharmaceuticals 2019, 12, 29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Woodburn, S.C.; Bollinger, J.L.; Wohleb, E.S. The semantics of microglia activation: Neuroinflammation, homeostasis, and stress. J. Neuroinflamm. 2021, 18, 258. [Google Scholar] [CrossRef]
  98. Hoogland, I.C.; Houbolt, C.; van Westerloo, D.J.; van Gool, W.A.; van de Beek, D. Systemic inflammation and microglial activation: Systematic review of animal experiments. J. Neuroinflamm. 2015, 12, 114. [Google Scholar] [CrossRef] [Green Version]
  99. Hoogland, I.C.M.; Westhoff, D.; Engelen-Lee, J.Y.; Melief, J.; Valls Seron, M.; Houben-Weerts, J.; Huitinga, I.; van Westerloo, D.J.; van der Poll, T.; van Gool, W.A.; et al. Microglial activation after systemic stimulation with lipopolysaccharide and escherichia coli. Front. Cell Neurosci. 2018, 12, 110. [Google Scholar] [CrossRef] [Green Version]
  100. Griton, M.; Dhaya, I.; Nicolas, R.; Raffard, G.; Periot, O.; Hiba, B.; Konsman, J.P. Experimental sepsis-associated encephalopathy is accompanied by altered cerebral blood perfusion and water diffusion and related to changes in cyclooxygenase-2 expression and glial cell morphology but not to blood-brain barrier breakdown. Brain Behav. Immun. 2020, 83, 200–213. [Google Scholar] [CrossRef]
  101. Rummel, C.; Inoue, W.; Poole, S.; Luheshi, G.N. Leptin regulates leukocyte recruitment into the brain following systemic lps-induced inflammation. Mol. Psychiatry 2010, 15, 523–534. [Google Scholar] [CrossRef] [PubMed]
  102. Cazareth, J.; Guyon, A.; Heurteaux, C.; Chabry, J.; Petit-Paitel, A. Molecular and cellular neuroinflammatory status of mouse brain after systemic lipopolysaccharide challenge: Importance of ccr2/ccl2 signaling. J. Neuroinflamm. 2014, 11, 132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Mori, Y.; Chen, T.; Fujisawa, T.; Kobashi, S.; Ohno, K.; Yoshida, S.; Tago, Y.; Komai, Y.; Hata, Y.; Yoshioka, Y. From cartoon to real time mri: In vivo monitoring of phagocyte migration in mouse brain. Sci. Rep. 2014, 4, 6997. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Denstaedt, S.J.; Spencer-Segal, J.L.; Newstead, M.; Laborc, K.; Zeng, X.; Standiford, T.J.; Singer, B.H. Persistent neuroinflammation and brain-specific immune priming in a novel survival model of murine pneumosepsis. Shock 2020, 54, 78–86. [Google Scholar] [CrossRef]
  105. Saito, M.; Fujinami, Y.; Ono, Y.; Ohyama, S.; Fujioka, K.; Yamashita, K.; Inoue, S.; Kotani, J. Infiltrated regulatory t cells and th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis. Brain Behav. Immun. 2021, 92, 25–38. [Google Scholar] [CrossRef]
  106. Ghazanfari, N.; Gregory, J.L.; Devi, S.; Fernandez-Ruiz, D.; Beattie, L.; Mueller, S.N.; Heath, W.R. Cd8(+) and cd4(+) t cells infiltrate into the brain during plasmodium berghei anka infection and form long-term resident memory. J. Immunol. 2021, 207, 1578–1590. [Google Scholar] [CrossRef]
  107. Eckman, P.L.; King, W.M.; Brunson, J.G. Studies on the blood brain barrier. I. Effects produced by a single injection of gramnegative endotoxin on the permeability of the cerebral vessels. Am. J. Pathol. 1958, 34, 631–643. [Google Scholar]
  108. Galea, I. The blood-brain barrier in systemic infection and inflammation. Cell Mol. Immunol. 2021, 18, 2489–2501. [Google Scholar] [CrossRef]
  109. Morimoto, A.; Murakami, N.; Nakamori, T.; Watanabe, T. Fever induced in rabbits by intraventricular injection of rabbit and human serum albumin. J. Physiol. 1987, 390, 137–144. [Google Scholar] [CrossRef]
  110. Steiner, A.A.; Ivanov, A.I.; Serrats, J.; Hosokawa, H.; Phayre, A.N.; Robbins, J.R.; Roberts, J.L.; Kobayashi, S.; Matsumura, K.; Sawchenko, P.E.; et al. Cellular and molecular bases of the initiation of fever. PLoS Biol. 2006, 4, e284. [Google Scholar] [CrossRef] [Green Version]
  111. Dhaya, I.; Griton, M.; Raffard, G.; Amri, M.; Hiba, B.; Konsman, J.P. Bacterial lipopolysaccharide-induced systemic inflammation alters perfusion of white matter-rich regions without altering flow in brain-irrigating arteries: Relationship to blood-brain barrier breakdown? J. Neuroimmunol. 2018, 314, 67–80. [Google Scholar] [CrossRef] [PubMed]
  112. Dhaya, I.; Griton, M.; Konsman, J.P. Magnetic resonance imaging under isoflurane anesthesia alters cortical cyclooxygenase-2 expression and glial cell morphology during sepsis-associated neurological dysfunction in rats. Anim. Model. Exp. Med. 2021, 4, 249–260. [Google Scholar] [CrossRef] [PubMed]
  113. Papadopoulos, M.C.; Lamb, F.J.; Moss, R.F.; Davies, D.C.; Tighe, D.; Bennett, E.D. Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex. Clin. Sci. 1999, 96, 461–466. [Google Scholar] [CrossRef]
  114. Sharshar, T.; Gray, F.; Poron, F.; Raphael, J.C.; Gajdos, P.; Annane, D. Multifocal necrotizing leukoencephalopathy in septic shock. Crit. Care Med. 2002, 30, 2371–2375. [Google Scholar] [CrossRef]
  115. Semmler, A.; Okulla, T.; Sastre, M.; Dumitrescu-Ozimek, L.; Heneka, M.T. Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J. Chem. Neuroanat. 2005, 30, 144–157. [Google Scholar] [CrossRef]
  116. Cunningham, C.; Wilcockson, D.C.; Campion, S.; Lunnon, K.; Perry, V.H. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 2005, 25, 9275–9284. [Google Scholar] [CrossRef] [Green Version]
  117. Calcia, M.A.; Bonsall, D.R.; Bloomfield, P.S.; Selvaraj, S.; Barichello, T.; Howes, O.D. Stress and neuroinflammation: A systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology 2016, 233, 1637–1650. [Google Scholar] [CrossRef] [Green Version]
  118. Chaaya, N.; Jacques, A.; Belmer, A.; Beecher, K.; Ali, S.A.; Chehrehasa, F.; Battle, A.R.; Johnson, L.R.; Bartlett, S.E. Contextual fear conditioning alter microglia number and morphology in the rat dorsal hippocampus. Front. Cell Neurosci. 2019, 13, 214. [Google Scholar] [CrossRef]
  119. Weber, M.D.; Godbout, J.P.; Sheridan, J.F. Repeated social defeat, neuroinflammation, and behavior: Monocytes carry the signal. Neuropsychopharmacology 2017, 42, 46–61. [Google Scholar] [CrossRef] [Green Version]
  120. Yin, W.; Gallagher, N.R.; Sawicki, C.M.; McKim, D.B.; Godbout, J.P.; Sheridan, J.F. Repeated social defeat in female mice induces anxiety-like behavior associated with enhanced myelopoiesis and increased monocyte accumulation in the brain. Brain Behav. Immun. 2019, 78, 131–142. [Google Scholar] [CrossRef]
  121. Menard, C.; Pfau, M.L.; Hodes, G.E.; Kana, V.; Wang, V.X.; Bouchard, S.; Takahashi, A.; Flanigan, M.E.; Aleyasin, H.; LeClair, K.B.; et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 2017, 20, 1752–1760. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Markoullis, K.; Sargiannidou, I.; Schiza, N.; Hadjisavvas, A.; Roncaroli, F.; Reynolds, R.; Kleopa, K.A. Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol. 2012, 123, 873–886. [Google Scholar] [CrossRef] [PubMed]
  123. Bergoffen, J.; Scherer, S.S.; Wang, S.; Scott, M.O.; Bone, L.J.; Paul, D.L.; Chen, K.; Lensch, M.W.; Chance, P.F.; Fischbeck, K.H. Connexin mutations in x-linked charcot-marie-tooth disease. Science 1993, 262, 2039–2042. [Google Scholar] [CrossRef] [PubMed]
  124. Nelles, E.; Butzler, C.; Jung, D.; Temme, A.; Gabriel, H.D.; Dahl, U.; Traub, O.; Stumpel, F.; Jungermann, K.; Zielasek, J.; et al. Defective propagation of signals generated by sympathetic nerve stimulation in the liver of connexin32-deficient mice. Proc. Natl. Acad. Sci. USA 1996, 93, 9565–9570. [Google Scholar] [CrossRef] [Green Version]
  125. Menichella, D.M.; Goodenough, D.A.; Sirkowski, E.; Scherer, S.S.; Paul, D.L. Connexins are critical for normal myelination in the cns. J. Neurosci. 2003, 23, 5963–5973. [Google Scholar] [CrossRef]
  126. Papaneophytou, C.P.; Georgiou, E.; Karaiskos, C.; Sargiannidou, I.; Markoullis, K.; Freidin, M.M.; Abrams, C.K.; Kleopa, K.A. Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination. Glia 2018, 66, 2589–2603. [Google Scholar] [CrossRef]
  127. Stavropoulos, F.; Georgiou, E.; Sargiannidou, I.; Kleopa, K.A. Dysregulation of blood-brain barrier and exacerbated inflammatory response in cx47-deficient mice after induction of eae. Pharmaceuticals 2021, 14, 621. [Google Scholar] [CrossRef]
  128. Bohmwald, K.; Andrade, C.A.; Kalergis, A.M. Contribution of pro-inflammatory molecules induced by respiratory virus infections to neurological disorders. Pharmaceuticals 2021, 14, 340. [Google Scholar] [CrossRef]
  129. Lemstra, A.W.; Groen in’t Woud, J.C.; Hoozemans, J.J.; van Haastert, E.S.; Rozemuller, A.J.; Eikelenboom, P.; van Gool, W.A. Microglia activation in sepsis: A case-control study. J. Neuroinflamm. 2007, 4, 4. [Google Scholar] [CrossRef] [Green Version]
  130. Munster, B.C.; Aronica, E.; Zwinderman, A.H.; Eikelenboom, P.; Cunningham, C.; Rooij, S.E. Neuroinflammation in delirium: A postmortem case-control study. Rejuvenation Res. 2011, 14, 615–622. [Google Scholar] [CrossRef] [Green Version]
  131. Polito, A.; Brouland, J.P.; Porcher, R.; Sonneville, R.; Siami, S.; Stevens, R.D.; Guidoux, C.; Maxime, V.; de la Grandmaison, G.L.; Chretien, F.C.; et al. Hyperglycaemia and apoptosis of microglial cells in human septic shock. Crit. Care 2011, 15, R131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Moraes, C.A.; Zaverucha-do-Valle, C.; Fleurance, R.; Sharshar, T.; Bozza, F.A.; d’Avila, J.C. Neuroinflammation in sepsis: Molecular pathways of microglia activation. Pharmaceuticals 2021, 14, 416. [Google Scholar] [CrossRef] [PubMed]
  133. Opal, S.M. The clinical relevance of endotoxin in human sepsis: A critical analysis. J. Endotoxin Res. 2002, 8, 473–476. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Yang, H.; Wang, H.; Andersson, U. Targeting inflammation driven by hmgb1. Front. Immunol. 2020, 11, 484. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Sunden-Cullberg, J.; Norrby-Teglund, A.; Rouhiainen, A.; Rauvala, H.; Herman, G.; Tracey, K.J.; Lee, M.L.; Andersson, J.; Tokics, L.; Treutiger, C.J. Persistent elevation of high mobility group box-1 protein (hmgb1) in patients with severe sepsis and septic shock. Crit. Care Med. 2005, 33, 564–573. [Google Scholar] [CrossRef] [PubMed]
  136. Wang, H.; Bloom, O.; Zhang, M.; Vishnubhakat, J.M.; Ombrellino, M.; Che, J.; Frazier, A.; Yang, H.; Ivanova, S.; Borovikova, L.; et al. Hmg-1 as a late mediator of endotoxin lethality in mice. Science 1999, 285, 248–251. [Google Scholar] [CrossRef]
  137. Laflamme, N.; Rivest, S. Toll-like receptor 4: The missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J. 2001, 15, 155–163. [Google Scholar] [CrossRef] [Green Version]
  138. Peek, V.; Harden, L.M.; Damm, J.; Aslani, F.; Leisengang, S.; Roth, J.; Gerstberger, R.; Meurer, M.; von Kockritz-Blickwede, M.; Schulz, S.; et al. Lps primes brain responsiveness to high mobility group box-1 protein. Pharmaceuticals 2021, 14, 558. [Google Scholar] [CrossRef]
  139. Stenken, J.A.; Poschenrieder, A.J. Bioanalytical chemistry of cytokines--a review. Anal. Chim. Acta 2015, 853, 95–115. [Google Scholar] [CrossRef]
  140. Kvivik, I.; Jonsson, G.; Omdal, R.; Brede, C. Sample preparation strategies for antibody-free quantitative analysis of high mobility group box 1 protein. Pharmaceuticals 2021, 14, 537. [Google Scholar] [CrossRef]
  141. Chaskiel, L.; Bristow, A.D.; Bluthe, R.M.; Dantzer, R.; Blomqvist, A.; Konsman, J.P. Interleukin-1 reduces food intake and body weight in rat by acting in the arcuate hypothalamus. Brain Behav. Immun. 2019, 81, 560–573. [Google Scholar] [CrossRef] [PubMed]
  142. Konsman, J.P.; Vigues, S.; Mackerlova, L.; Bristow, A.; Blomqvist, A. Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: Relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J. Comp. Neurol. 2004, 472, 113–129. [Google Scholar] [CrossRef] [PubMed]
  143. Chaskiel, L.; Dantzer, R.; Konsman, J.P. Brain perivascular macrophages do not mediate interleukin-1-induced sickness behavior in rats. Pharmaceuticals 2021, 14, 1030. [Google Scholar] [CrossRef] [PubMed]
  144. Rankin, S.M.; Conroy, D.M.; Williams, T.J. Eotaxin and eosinophil recruitment: Implications for human disease. Mol. Med. Today 2000, 6, 20–27. [Google Scholar] [CrossRef]
  145. Chang, E.E.; Chung, L.Y.; Yen, C.M. Kinetics of change in the eotaxin concentration in serum and cerebrospinal fluid of mice infected with angiostrongylus cantonensis. Parasitol. Res. 2004, 92, 137–141. [Google Scholar] [CrossRef]
  146. Intapan, P.M.; Niwattayakul, K.; Sawanyawisuth, K.; Chotmongkol, V.; Maleewong, W. Cerebrospinal fluid eotaxin and eotaxin-2 levels in human eosinophilic meningitis associated with angiostrongyliasis. Cytokine 2007, 39, 138–141. [Google Scholar] [CrossRef]
  147. Shurin, G.V.; Yurkovetsky, Z.R.; Chatta, G.S.; Tourkova, I.L.; Shurin, M.R.; Lokshin, A.E. Dynamic alteration of soluble serum biomarkers in healthy aging. Cytokine 2007, 39, 123–129. [Google Scholar] [CrossRef]
  148. Erickson, M.A.; Morofuji, Y.; Owen, J.B.; Banks, W.A. Rapid transport of ccl11 across the blood-brain barrier: Regional variation and importance of blood cells. J. Pharmacol. Exp. Ther. 2014, 349, 497–507. [Google Scholar] [CrossRef] [Green Version]
  149. Ivanovska, M.; Abdi, Z.; Murdjeva, M.; Macedo, D.; Maes, A.; Maes, M. Ccl-11 or eotaxin-1: An immune marker for ageing and accelerated ageing in neuro-psychiatric disorders. Pharmaceuticals 2020, 13, 230. [Google Scholar] [CrossRef]
  150. Teixeira, A.L.; Gama, C.S.; Rocha, N.P.; Teixeira, M.M. Revisiting the role of eotaxin-1/ccl11 in psychiatric disorders. Front. Psychiatry 2018, 9, 241. [Google Scholar] [CrossRef]
  151. Burgener, I.; Van Ham, L.; Jaggy, A.; Vandevelde, M.; Tipold, A. Chemotactic activity and il-8 levels in the cerebrospinal fluid in canine steroid responsive meningitis-arteriitis. J. Neuroimmunol. 1998, 89, 182–190. [Google Scholar] [CrossRef]
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Konsman, J.P. Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire! Pharmaceuticals 2022, 15, 140. https://doi.org/10.3390/ph15020140

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Konsman JP. Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire! Pharmaceuticals. 2022; 15(2):140. https://doi.org/10.3390/ph15020140

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Konsman, Jan Pieter. 2022. "Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire!" Pharmaceuticals 15, no. 2: 140. https://doi.org/10.3390/ph15020140

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