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Neuroimmune Interactions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 29179

Special Issue Editor

Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA
Interests: microglia; neuroimmune interactions; models of disease; neurodegeneration; innate immunity; crosstalk
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Once thought to be “immune privileged” and excluded from systemic surveillance, the nervous system is becoming recognized as having active communication with the immune system. Increasing recent evidence suggests specific mechanisms of monitoring of both central and peripheral nervous systems by local immune cells, the microglia, as well as by the dendritic cells, previously thought only as peripheral antigen-presenting cells, which act as messengers between the innate and the adaptive immune systems. In this Special Issue, we will examine aspects of this communication between the brain, spinal cord and the immune system, and follow their interactions in the normal, healthy, physiological nervous system, as well as during pathological events and conditions.

Prof. Styliani-Anna (Stella) E. Tsirka
Guest Editor

Manuscript Submission Information

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Keywords

  • microglia
  • antigen-presenting cells
  • innate immunity
  • adaptive immunity
  • blood-brain-carrier
  • ventricles
  • neurodegenerative disease
  • glymphatics

 

Published Papers (7 papers)

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Research

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22 pages, 1594 KiB  
Article
Early-Life Maternal Deprivation Predicts Stronger Sickness Behaviour and Reduced Immune Responses to Acute Endotoxaemia in a Pig Model
by Roberto Brückmann, Margret Tuchscherer, Armin Tuchscherer, Ulrike Gimsa and Ellen Kanitz
Int. J. Mol. Sci. 2020, 21(15), 5212; https://doi.org/10.3390/ijms21155212 - 23 Jul 2020
Cited by 9 | Viewed by 2401
Abstract
Early-life adversity may have programming effects on neuroendocrine and immune adaptation mechanisms in humans and socially living animals. Using a pig model, we investigated the effect of daily 2-h maternal and littermate deprivation from postnatal days 2–15, either alone (DA) or in a [...] Read more.
Early-life adversity may have programming effects on neuroendocrine and immune adaptation mechanisms in humans and socially living animals. Using a pig model, we investigated the effect of daily 2-h maternal and littermate deprivation from postnatal days 2–15, either alone (DA) or in a group of littermates (DG) on the neuroendocrine, immunological and behavioural responses of piglets challenged with the bacterial endotoxin lipopolysaccharide (LPS) on day 42. LPS increased plasma concentrations of cortisol, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) and induced typical signs of sickness in all piglets. DA+DG piglets showed stronger signs of sickness compared to control (C) piglets. Plasma TNF-α concentrations were significantly lower in DA+DG males. In addition, the TNF-α/IL-10 ratio was significantly lower in DA than in DG and C males. Gene expression analyses showed lower hypothalamic TNF-α mRNA expression and diminished mRNA expression of the mineralocorticoid receptor (MR) and IL-10 in the amygdala of DA+DG piglets in response to LPS. Interestingly, males showed a higher MR- and a lower IL-10 mRNA expression in the amygdala than females. The present data suggest that repeated maternal deprivation during early life may alter neuroendocrine and immune responses to acute endotoxaemia in a sex-specific manner. Full article
(This article belongs to the Special Issue Neuroimmune Interactions)
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24 pages, 3066 KiB  
Article
Differential Expression of Neuroinflammatory mRNAs in the Rat Sciatic Nerve Following Chronic Constriction Injury and Pain-Relieving Nanoemulsion NSAID Delivery to Infiltrating Macrophages
by Andrea M. Stevens, Lu Liu, Dylan Bertovich, Jelena M. Janjic and John A. Pollock
Int. J. Mol. Sci. 2019, 20(21), 5269; https://doi.org/10.3390/ijms20215269 - 24 Oct 2019
Cited by 23 | Viewed by 4158
Abstract
The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic [...] Read more.
The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Cav2.2, Itgam/Cd11b, Scn9a/Nav1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE2 at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain. Full article
(This article belongs to the Special Issue Neuroimmune Interactions)
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15 pages, 2423 KiB  
Article
The Expression of the Chemokine CXCL14 Correlates with Several Aggressive Aspects of Glioblastoma and Promotes Key Properties of Glioblastoma Cells
by Barbara Fazi, Carla Proserpio, Silvia Galardi, Francesca Annesi, Mattia Cola, Annunziato Mangiola, Alessandro Michienzi and Silvia Anna Ciafrè
Int. J. Mol. Sci. 2019, 20(10), 2496; https://doi.org/10.3390/ijms20102496 - 21 May 2019
Cited by 21 | Viewed by 3538
Abstract
Glioblastoma (GBM) is a primary brain tumor whose prognosis is inevitably dismal, leading patients to death in about 15 months from diagnosis. Tumor cells in the mass of the neoplasm are in continuous exchange with cells of the stromal microenvironment, through the production [...] Read more.
Glioblastoma (GBM) is a primary brain tumor whose prognosis is inevitably dismal, leading patients to death in about 15 months from diagnosis. Tumor cells in the mass of the neoplasm are in continuous exchange with cells of the stromal microenvironment, through the production of soluble molecules, among which chemokines play prominent roles. CXCL14 is a chemokine with a pro-tumor role in breast and prostate carcinoma, where it is secreted by cancer associated fibroblasts, and contributes to tumor growth and invasion. We previously observed that CXCL14 expression is higher in GBM tissues than in healthy white matter. Here, we study the effects of exogenously supplemented CXCL14 on key tumorigenic properties of human GBM cell lines. We show that CXCL14 enhances the migration ability and the proliferation of U87MG and LN229 GBM cell lines. None of these effects was affected by the use of AMD3100, an inhibitor of CXCR4 receptor, suggesting that the observed CXCL14 effects are not mediated by this receptor. We also provide evidence that CXCL14 enhances the sphere-forming ability of glioblastoma stem cells, considered the initiating cells, and is responsible for tumor onset, growth and recurrence. In support of our in vitro results, we present data from several GBM expression datasets, demonstrating that CXCL14 expression is inversely correlated with overall survival, that it is enriched at the leading edge of the tumors and in infiltrating tumor areas, and it characterizes mesenchymal and NON G-CIMP tumors, known to have a particularly bad prognosis. Overall, our results point to CXCL14 as a protumorigenic chemokine in GBM. Full article
(This article belongs to the Special Issue Neuroimmune Interactions)
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12 pages, 5551 KiB  
Article
Attenuating Diabetic Vascular and Neuronal Defects by Targeting P2rx7
by Sofia Pavlou, Josy Augustine, Rónán Cunning, Kevin Harkin, Alan W. Stitt, Heping Xu and Mei Chen
Int. J. Mol. Sci. 2019, 20(9), 2101; https://doi.org/10.3390/ijms20092101 - 29 Apr 2019
Cited by 17 | Viewed by 3830
Abstract
Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value [...] Read more.
Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value in preventing the early stages of diabetic retinopathy. Here, we show that the nucleoside reverse transcriptase inhibitor lamivudine (3TC), a newly discovered P2rx7 inhibitor, can attenuate progression of both neuronal and vascular pathology in diabetic retinopathy. We found that the expression of P2rx7 was increased in the murine retina as early as one month following diabetes induction. Compared to non-diabetic controls, diabetic mice treated with 3TC were protected against the formation of acellular capillaries in the retina. This occurred concomitantly with a maintenance in neuroglial function, as shown by improved a- and b-wave amplitude, as well as oscillatory potentials. An improvement in the number of GABAergic amacrine cells and the synaptophysin-positive area was also observed in the inner retina of 3TC-treated diabetic mice. Our data suggest that 3TC has therapeutic potential since it can target both neuronal and vascular defects caused by diabetes. Full article
(This article belongs to the Special Issue Neuroimmune Interactions)
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Review

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17 pages, 686 KiB  
Review
Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment
by Daniel P. Radin and Stella E. Tsirka
Int. J. Mol. Sci. 2020, 21(22), 8476; https://doi.org/10.3390/ijms21228476 - 11 Nov 2020
Cited by 49 | Viewed by 6488
Abstract
Despite significant strides made in understanding the pathophysiology of high-grade gliomas over the past two decades, most patients succumb to these neoplasias within two years of diagnosis. Furthermore, there are various co-morbidities associated with glioma and standard of care treatments. Emerging evidence suggests [...] Read more.
Despite significant strides made in understanding the pathophysiology of high-grade gliomas over the past two decades, most patients succumb to these neoplasias within two years of diagnosis. Furthermore, there are various co-morbidities associated with glioma and standard of care treatments. Emerging evidence suggests that aberrant glutamate secretion in the glioma microenvironment promotes tumor progression and contributes to the development of co-morbidities, such as cognitive defects, epilepsy, and widespread neurodegeneration. Recent data clearly illustrate that neurons directly synapse onto glioma cells and drive their proliferation and spread via glutamatergic action. Microglia are central nervous system-resident myeloid cells, modulate glioma growth, and possess the capacity to prune synapses and encourage synapse formation. However, current literature has yet to investigate the potential role of microglia in shaping synapse formation between neurons and glioma cells. Herein, we present the literature concerning glutamate’s role in glioma progression, involving hyperexcitability and excitotoxic cell death of peritumoral neurons and stimulation of glioma proliferation and invasion. Furthermore, we discuss instances in which microglia are more likely to sculpt or encourage synapse formation during glioma treatment and propose studies to delineate the role of microglia in synapse formation between neurons and glioma cells. The sex-dependent oncogenic or oncolytic actions of microglia and myeloid cells, in general, are considered in addition to the functional differences between microglia and macrophages in tumor progression. We also put forth tractable methods to safely perturb aberrant glutamatergic action in the tumor microenvironment without significantly increasing the toxicities of the standard of care therapies for glioma therapy. Full article
(This article belongs to the Special Issue Neuroimmune Interactions)
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27 pages, 801 KiB  
Review
Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration
by Mohammed Al-Onaizi, Alaa Al-Khalifah, Dalal Qasem and Ayman ElAli
Int. J. Mol. Sci. 2020, 21(18), 6875; https://doi.org/10.3390/ijms21186875 - 19 Sep 2020
Cited by 21 | Viewed by 4093
Abstract
Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells [...] Read more.
Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases. Full article
(This article belongs to the Special Issue Neuroimmune Interactions)
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20 pages, 1706 KiB  
Review
Environmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease
by Luana da Silva Chagas, Poliana Capucho Sandre, Natalia Cristina Aparecida Ribeiro e Ribeiro, Henrique Marcondes, Priscilla Oliveira Silva, Wilson Savino and Claudio A. Serfaty
Int. J. Mol. Sci. 2020, 21(6), 2111; https://doi.org/10.3390/ijms21062111 - 19 Mar 2020
Cited by 22 | Viewed by 4126
Abstract
Recent discoveries on the neurobiology of the immunocompetent cells of the central nervous system (CNS), microglia, have been recognized as a growing field of investigation on the interactions between the brain and the immune system. Several environmental contexts such as stress, lesions, infectious [...] Read more.
Recent discoveries on the neurobiology of the immunocompetent cells of the central nervous system (CNS), microglia, have been recognized as a growing field of investigation on the interactions between the brain and the immune system. Several environmental contexts such as stress, lesions, infectious diseases, and nutritional and hormonal disorders can interfere with CNS homeostasis, directly impacting microglial physiology. Despite many encouraging discoveries in this field, there are still some controversies that raise issues to be discussed, especially regarding the relationship between the microglial phenotype assumed in distinct contexts and respective consequences in different neurobiological processes, such as disorders of brain development and neuroplasticity. Also, there is an increasing interest in discussing microglial–immune system cross-talk in health and in pathological conditions. In this review, we discuss recent literature concerning microglial function during development and homeostasis. In addition, we explore the contribution of microglia to synaptic disorders mediated by different neuroinflammatory outcomes during pre- and postnatal development, with long-term consequences impacting on the risk and vulnerability to the emergence of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Neuroimmune Interactions)
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