Direct Transfer of ��-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Abnormal neuronal aggregation of α-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive α-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial α-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that α-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of α-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human α-synuclein. Furthermore, astrocytes that were exposed to neuronal α-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of α-synuclein. Together, these results suggest that astroglial α-synuclein pathology is produced by direct transmission of neuronal α-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.     

Analysis of the neuroinflammatory response to TLR7 stimulation in the brain: comparison of multiple TLR7 and/or TLR8 agonists

Activation of astrocytes and microglia and the production of proinflammatory cytokines and chemokines are often associated with virus infection in the CNS as well as a number of neurological diseases of unknown etiology. These inflammatory responses may be initiated by recognition of pathogen-associated molecular patterns (PAMPs) that stimulate TLRs. TLR7 and TLR8 were identified as eliciting antiviral effects when stimulated by viral ssRNA. In the present study, we examined the potential of TLR7 and/or TLR8 agonists to induce glial activation and neuroinflammation in the CNS by intracerebroventricular inoculation of TLR7 and/or TLR8 agonists in newborn mice. The TLR7 agonist imiquimod induced astrocyte activation and up-regulation of proinflammatory cytokines and chemokines, including IFN-beta, TNF, CCL2, and CXCL10. However, these responses were only of short duration when compared with responses induced by the TLR4 agonist LPS. Interestingly, some of the TLR7 and/or TLR8 agonists differed in their ability to activate glial cells as evidenced by their ability to induce cytokine and chemokine expression both in vivo and in vitro. Thus, TLR7 stimulation can induce neuroinflammatory responses in the brain, but individual TLR7 agonists may differ in their ability to stimulate cells of the CNS.     

Solid-phase and bead-based cytokine immunoassay: a comparison

Cytokines and chemoattractive cytokines (chemokines) are present in a wide variety of body fluids such as plasma, cerebrospinal fluid, bronchoaveolar fluid, amniotic fluid, synovial fluid, middle ear effusion fluid, and urine. Cytokines can be detected using classical solid-phase sandwich immunoassays such as enzyme-linked immunosorbent assay (ELISA) or with a bead based multiplex immunoassay (MIA). The physical chemical properties of the different body fluids (such as pH and total protein content) differ, which may have an impact on the outcome of the cytokine assay. Both ELISA as well as MIA cytokine detection systems are constructed by sandwiching the protein of interest between a capture and reporter antibody. When the biological sample contains heterophilic antibodies (such as in patients with auto-immune diseases), these non-specific antibodies can cause false positive results. During pathological conditions, cytokines may be found over a wide concentration range; likewise have to cover this dynamic range in a similar fashion. The correct (statistical) analysis of standard curves and (multiplexed) data are critical for proper interpretation. Classical ELISA based cytokine assays are robust, easy to use and very well suited for measurement of single cytokines. Due to an increased interest in the integral approach to understand biological processes (the omics era), multiplex immunoassays for detection of cytokines and the interpretation of these assays are gaining popularity.     

Analysis of Plasma Cytokine and Chemokine Profiles in Patients with and without Tuberculosis by Liquid Array-Based Multiplexed Immunoassays

The aim of this study was to establish plasma cytokine/chemokine profiles in patients with 3 different presentations of active tuberculosis (TB), compared to the profiles observed in bacillus Calmette-Guérin (BCG)-vaccinated healthy individuals and patients with other pulmonary diseases (non-TB patients). To this end, plasma samples were collected from 151 TB patients including 68 pulmonary TB (PTB), 43 endobronchial TB, and 40 tuberculosis pleurisy (TP) patients, as well as 107 no-TB cases including 26 non-TB patients and 81 BCG-vaccinated healthy controls. A liquid array-based multiplexed immunoassay was used to screen plasma samples for 20 distinct cytokines and chemokines. Multinomial logistic regression was used to analyze associations between cytokines/chemokines and TB/non-TB patients. Compared to our findings with the no-TB donors, the median plasma levels of the proinflammatory cytokines/chemokines TNF-α, IL-6, IP-10, IFN-γ, and MIP-1β were significantly elevated in TB patients, suggesting their potential use as biomarkers for diagnosing TB patients. Further comparisons with healthy donors showed that only the median TNF-α plasma level was highly produced in the plasma of all 3 types of TB patients. Plasma IL-6 production was higher only in TP patients, while the plasma levels of IP-10, IFN-γ, and MIP-1β were markedly enhanced in both PTB and TP patients. Unexpectedly, among the above cytokines/chemokines, MIP-1β was also highly expressed in non-TB patients, compared with healthy donors. Our results suggested that TNF-α may be an ideal biomarker for diagnosing the 3 forms of TB presentation, while the other factors (IL-6, IP-10, MCP-1, and IFN-γ) can potentially facilitate differential diagnosis for the 3 TB presentation types. Further characterization of immune responses associated with different types of TB diseases will provide a basis for developing novel TB diagnostics.     

Cytokines and cytokine networks target neurons to modulate long-term potentiation

Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines.     

Characteristic Cerebrospinal Fluid Cytokine/Chemokine Profiles in Neuromyelitis Optica,Relapsing Remitting or Primary Progressive Multiple Sclerosis

Background

Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO), relapsing remitting multiple sclerosis (RRMS), and primary progressive MS (PPMS), and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis.

Methods/Principal Findings

We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND) by multiplexed fluorescent bead-based immunoassay. Interleukin (IL)-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF) and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-γ, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients.

Conclusions

Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell and macrophage/microglia inflammation in the central nervous system. In RRMS, only a mild elevation of proinflammatory cytokines/chemokines was detectable at relapse.     

Polyunsaturated fatty acids,neuroinflammation and well being

The innate immune system of the brain is principally composed of microglial cells and astrocytes, which, once activated, protect neurons against insults (infectious agents, lesions, etc.). Activated glial cells produce inflammatory cytokines that act specifically through receptors expressed by the brain. The functional consequences of brain cytokine action (also called neuroinflammation) are alterations in cognition, mood and behaviour, a hallmark of altered well-being. In addition, proinflammatory cytokines play a key role in depression and neurodegenerative diseases linked to aging. Polyunsaturated fatty acids (PUFA) are essential nutrients and essential components of neuronal and glial cell membranes. PUFA from the diet regulate both prostaglandin and proinflammatory cytokine production. n-3 fatty acids are anti-inflammatory while n-6 fatty acids are precursors of prostaglandins. Inappropriate amounts of dietary n-6 and n-3 fatty acids could lead to neuroinflammation because of their abundance in the brain and reduced well-being. Depending on which PUFA are present in the diet, neuroinflammation will, therefore, be kept at a minimum or exacerbated. This could explain the protective role of n-3 fatty acids in neurodegenerative diseases linked to aging.     

Non-Neuronal Cells Are Required to Mediate the Effects of Neuroinflammation: Results from a Neuron-Enriched Culture System

Chronic inflammation is associated with activated microglia and reactive astrocytes and plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s. Both in vivo and in vitro studies have demonstrated that inflammatory cytokine responses to immune challenges contribute to neuronal death during neurodegeneration. In order to investigate the role of glial cells in this phenomenon, we developed a modified method to remove the non-neuronal cells in primary cultures of E16.5 mouse cortex. We modified previously reported methods as we found that a brief treatment with the thymidine analog, 5-fluorodeoxyuridine (FdU), is sufficient to substantially deplete dividing non-neuronal cells in primary cultures. Cell cycle and glial markers confirm the loss of ~99% of all microglia, astrocytes and oligodendrocyte precursor cells (OPCs). More importantly, under this milder treatment, the neurons suffered neither cell loss nor any morphological defects up to 2.5 weeks later; both pre- and post-synaptic markers were retained. Further, neurons in FdU-treated cultures remained responsive to excitotoxicity induced by glutamate application. The immunobiology of the FdU culture, however, was significantly changed. Compared with mixed culture, the protein levels of NFκB p65 and the gene expression of several cytokine receptors were altered. Individual cytokines or conditioned medium from β-amyloid-stimulated THP-1 cells that were, potent neurotoxins in normal, mixed cultures, were virtually inactive in the absence of glial cells. The results highlight the importance of our glial-depleted culture system and identifies and offer unexpected insights into the complexity of -brain neuroinflammation.     

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

Spinal cord injury (SCI) is a complex debilitating condition leading to permanent life-long neurological deficits. The complexity of SCI suggests that a concerted multi-targeted therapeutic approach is warranted to optimally improve function. Damage to spinal cord is complicated by an increased detrimental response from secondary injury factors mediated by activated glial cells and infiltrating macrophages. While elevation of enolase especially neuron specific enolase (NSE) in glial and neuronal cells is believed to trigger inflammatory cascades in acute SCI, alteration of NSE and its subsequent effects in acute SCI remains unknown. This study measured NSE expression levels and key inflammatory mediators after acute SCI and investigated the role of ENOblock, a novel small molecule inhibitor of enolase, in a male Sprague–Dawley (SD) rat SCI model. Serum NSE levels as well as cytokines/chemokines and metabolic factors were evaluated in injured animals following treatment with vehicle alone or ENOblock using Discovery assay. Spinal cord samples were also analyzed for NSE and MMPs 2 and 9 as well as glial markers by Western blotting. The results indicated a significant decrease in serum inflammatory cytokines/chemokines and NSE, alterations of metabolic factors and expression of MMPs in spinal cord tissues after treatment with ENOblock (100 µg/kg, twice). These results support the hypothesis that activation of glial cells and inflammation status can be modulated by regulation of NSE expression and activity. Analysis of SCI tissue samples by immunohistochemistry confirmed that ENOblock decreased gliosis which may have occurred through reduction of elevated NSE in rats. Overall, elevation of NSE is deleterious as it promotes extracellular degradation and production of inflammatory cytokines/chemokines and metabolic factors which activates glia and damages neurons. Thus, reduction of NSE by ENOblock may have potential therapeutic implications in acute SCI.     

Enhanced Expression of Glia Maturation Factor Correlates with Glial Activation in the Brain of Triple Transgenic Alzheimer’s Disease Mice

We previously demonstrated that glia maturation factor (GMF), a brain specific protein, isolated, sequenced and cloned in our laboratory, induce expression of proinflammatory cytokines and chemokines in the central nervous system. We also reported that the up-regulation of GMF in astrocytes leads to the destruction of neurons suggesting a novel pathway of GMF-mediated cytotoxicity of brain cells, and implicated its involvement in the pathogenesis of inflammatory neurodegenerative diseases. In the present study, we examined the expressions of GMF in triple-transgenic Alzheimer’s disease (3xTg-AD) mice. Our results show a 13-fold up-regulation of GMF and 8–12-fold up-regulation of proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, interferon gamma (IFN-γ), and chemokine (C–C motif) ligand 2 (CCL2) and C–X–C motif chemokine 10 (CXCL10/IP-10) mRNA as determined by quantitative real-time RT-PCR in the brain of 3xTg-AD mice as compared to non-transgenic (Non-Tg) mice. In conclusion, the increase in GMF and cytokine/chemokine expression was correlated with reactive glial fibrillary acidic protein positive astrocytes and ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglia in 3xTg-AD mice.     

Interleukin-6, a Major Cytokine in the Central Nervous System

Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.     

Coordinate expression of cytokines and chemokines by NK cells during murine cytomegalovirus infection

Cytokines and chemokines activate and direct effector cells during infection. We previously identified a functional group of five cytokines and chemokines, namely, IFN-gamma, activation-induced T cell-derived and chemokine-related cytokine/lymphotactin, macrophage-inflammatory protein 1alpha, macrophage-inflammatory protein 1beta, and RANTES, coexpressed in individual activated NK cells, CD8(+) T cells, and CD4(+) Th1 cells in vitro and during in vivo infections. However, the stimuli during infection were not known. In murine CMV (MCMV) infection, the DAP12/KARAP-associated Ly49H NK cell activation receptor is crucial for resistance through recognition of MCMV-encoded m157 but NK cells also undergo in vivo nonspecific responses to uncharacterized stimuli. In this study, we show that Ly49H ligation by m157 resulted in a coordinated release of all five cytokines/chemokines from Ly49H(+) NK cells. Whereas other cytokines also triggered the release of these cytokines/chemokines, stimulation was not confined to the Ly49H(+) population. At the single-cell level, the production of the five mediators showed strong positive correlation with each other. Interestingly, NK cells were a major source of these five cytokines/chemokines in vitro and in vivo, whereas infected macrophages produced only limited amounts of macrophage-inflammatory protein 1alpha, macrophage-inflammatory protein1beta, and RANTES. These findings suggest that both virus-specific and nonspecific NK cells play crucial roles in activating and directing other inflammatory cells during MCMV infection.     

Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer's disease

The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, and their effects in neurodegenerative diseases remain uncertain. Alzheimer's disease (AD) is a neurodegenerative disorder defined by misfolded protein accumulation with concurrent neuroinflammation and neuronal death. We report suppression of proteinase-activated receptor-2 (PAR2) expression in neurons of brains from AD patients, whereas PAR2 expression was increased in proximate glial cells, together with up-regulation of proinflammatory cytokines and chemokines and reduced IL-4 expression (p < 0.05). Glial PAR2 activation increased expression of formyl peptide receptor-2 (p < 0.01), a cognate receptor for a fibrillar 42-aa form of beta-amyloid (Abeta(1-42)), enhanced microglia-mediated proinflammatory responses, and suppressed astrocytic IL-4 expression, resulting in neuronal death (p < 0.05). Conversely, neuronal PAR2 activation protected human neurons against the toxic effects of Abeta(1-42) (p < 0.05), a key component of AD neuropathogenesis. Amyloid precursor protein-transgenic mice, displayed glial fibrillary acidic protein and IL-4 induction (p < 0.05) in the absence of proinflammatory gene up-regulation and neuronal injury, whereas PAR2 was up-regulated at this early stage of disease progression. PAR2-deficient mice, after hippocampal Abeta(1-42) implantation, exhibited enhanced IL-4 induction and less neuroinflammation (p < 0.05), together with improved neurobehavioral outcomes (p < 0.05). Thus, PAR2 exerted protective properties in neurons, but its activation in glia was pathogenic with secretion of neurotoxic factors and suppression of astrocytic anti-inflammatory mechanisms contributing to Abeta(1-42)-mediated neurodegeneration.     

RNAi Screen Reveals Potentially Novel Roles of Cytokines in Myoblast Differentiation

Cytokines are cell-secreted signaling molecules that modulate various cellular functions, with the best-characterized roles in immune responses. The expression of numerous cytokines in skeletal muscle tissues and muscle cells has been reported, but their function in skeletal myogenesis, the formation of skeletal muscle, has been largely underexplored. To systematically examine the potential roles of cytokines in skeletal myogenesis, we undertook an RNAi screen of 134 mouse cytokine genes for their involvement in the differentiation of C2C12 myoblasts. Our results have uncovered 29 cytokines as strong candidates for novel myogenic regulators, potentially conferring positive and negative regulation at distinct stages of myogenesis. These candidates represent a diverse collection of cytokine families, including interleukins, TNF-related factors, and chemokines. Our findings suggest the fundamental importance of cytokines in the cell-autonomous regulation of myoblast differentiation, and may facilitate future identification of novel therapeutic targets for improving muscle regeneration and growth in health and diseases.     

The cytokine-prostaglandin cascade in fever production: fact or fancy?

(1) The classical view of the genesis of infectious fevers is that they develop in sequential steps, starting with the production by peripheral mononuclear phagocytes activated by the infectious noxa (i.e., the invading pathogens and/or their products, e.g., bacterial endotoxic lipopolysaccharides (LPS)) of pyrogenic cytokines, principally tumor necrosis factor-, interleukin(IL)-1β and IL-6, the release of these cytokines into the bloodstream, their transport to targets accessible from blood (e.g., cerebral microvessels, the organum vasculosum laminae terminalis) in close proximity to the ventromedial preoptic area (VMPO, the presumptive brain site of the febrigenic controller), and the consequent generation of stimulatory signals directed to the VMPO. An alternative view is that the message of the pyrogenic cytokines elaborated in the periphery is conveyed to the VMPO via a neural rather than a humoral pathway. In both views, cyclooxygenase (COX)-2-dependent prostaglandin (PG) E₂ is considered to be the proximal fever mediator induced in the VMPO by these cytokines, modulating the activity of thermosensitive neurons contained in this region and effecting the development of fever. (2) However, peripheral cytokines are not consistently detectable in febrile illnesses, and it was recently reported that neither circulating LPS nor cytokine levels are increased at the onset of robust fevers induced in rats by subcutaneous injections of replicating Escherichia coli. (3) And it was reported long ago that the intracerebroventricular (icv) injection of PGE₂ did not evoke fever in newborn lambs and goats although these animals responded normally to the intravenous injection of LPS, and that the icv-injection of synthetic PGE₂ antagonists that prevented the febrile response of rabbits to icv-injected PGE₂ did not inhibit that to a simultaneously injected endogenous pyrogen. (4) Other, more recent data indicate that the pyrogenic chemokine macrophage inflammatory protein-1β produces fever independently of PGE₂. (5) We found recently that the febrile response of adult guinea pigs to intravenously injected LPS is initiated significantly before the appearance of cytokines in the blood and, moreover, is evoked and sustainable in the absence of preoptic PGE₂. (6) What is amiss? Are the contradictory data fallacious or should the conventional wisdom be revisited? This issue is considered in this article and an explanation suggested for these disparate findings.     

Neuronal stem cells in the central nervous system and in human diseases

The process of cortical expansion in the central nervous system is a key step of mammalian brain development to ensure its physiological function. Radial glial (RG) cells are a glial cell type contributing to this progress as intermediate neural progenitor cells responsible for an increase in the number of cortical neurons. In this review, we discuss the current understanding of RG cells during neurogenesis and provide further information on the mechanisms of neurodevelopmental diseases and stem cell-related brain tumorigenesis. Knowledge of neuronal stem cell and relative diseases will bridge benchmark research through translational studies to clinical therapeutic treatments of these diseases.     

Uterine and serum cytokine arrays in the mouse during estrus

Cytokines govern uterine immunology and embryo receptivity and are increasingly recognized for their embryotrophic roles. While supplementing culture media with cytokines may improve embryo development/viability in vitro, little is known about their physiological profiles in vivo, and hence which are likely to be uterine immunoregulators and embryotrophins. Therefore, this study profiled 23 cytokines in uterine fluid and serum from individual naturally cycling estrous mice. Samples were analyzed by fluid-phase multiplex immunoassays for interleukin (IL)-1, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17, eotaxin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon (IFN)-γ, keratinocyte-derived chemokine (KC), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 MIP)-1β regulated upon activation, normal T-cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-. There was a marked divergence in cytokine concentrations between uterine fluid and serum. The former was dominated by G-CSF, eotaxin, KC and IL-1, and had significantly higher levels of IL-1β, IL-2, IL-3, IL-4, IL-6, IL-9, GM-CSF, MIP-1, MIP-1β and RANTES. Serum had significantly higher IL-12 (p40), IL-12 (p70), IL-17 and IFN-γ concentrations. No significant differences in IL-5, IL-10, IL-13, MCP-1 or TNF- profiles were noted. These data indicated a strict compartmentalization of uterine cytokines, with G-CSF as a major cytokine at estrous. Results are discussed with respect to immune cell function, post-coital paternal antigen processing, estrous cyclicity, and endometrial angiogenesis, cell turnover and differentiation.     

Chemokines and Glial Cells: A Complex Network in the Central Nervous System

Chemokines are small secreted proteins that are essential for the recruitment and activation of specific leukocyte subsets at sites of inflammation and for the development and homeostasis of lymphoid and nonlymphoid tissues. During the past decade, chemokines and their receptors have also emerged as key signaling molecules in neuroinflammatory processes and in the development and functioning of the central nervous system. Neurons and glial cells, including astrocytes, oligodendrocytes, and microglia, have been identified as cellular sources and/or targets of chemokines produced in the central nervous system in physiological and pathological conditions. In this article, we provide an update of chemokines and chemokine receptors expressed by glial cells focusing on their biological functions and implications in neurological diseases.