Central Nervous System Resident Cells Research Articles

Peripheral monocytes are functionally altered and invade the CNS in ALS patients.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease affecting primarily the upper and lower motor neurons. A common feature of all ALS cases is a well-characterized neuroinflammatory reaction within the central nervous system (CNS). However, much less is known about the role of the peripheral immune system and its interplay with CNS resident immune cells in motor neuron degeneration. Here, we characterized peripheral monocytes in both temporal and spatial dimensions of ALS pathogenesis. We found the circulating monocytes to be deregulated in ALS regarding subtype constitution, function and gene expression. Moreover, we show that CNS infiltration of peripheral monocytes correlates with improved motor neuron survival in a genetic ALS mouse model. Furthermore, application of human immunoglobulins or fusion proteins containing only the human Fc, but not the Fab antibody fragment, increased CNS invasion of peripheral monocytes and delayed the disease onset. Our results underline the importance of peripheral monocytes in ALS pathogenesis and are in agreement with a protective role of monocytes in the early phase of the disease. The possibility to boost this beneficial function of peripheral monocytes by application of human immunoglobulins should be evaluated in clinical trials.

Role of astrocytes and microglia in central nervous system inflammation. Introduction.

The role of the adaptive immune system in autoimmune inflammatory diseases of the central nervous system (CNS) has been strongly investigated during the past decades. However, a growing body of evidence supports the importance of CNS resident glial populations in the initiation, propagation, and regulation of inflammation. To provide insight into this fascina t ing deve lopment , th i s i s sue of Seminars in Immunopathology focuses on the functions of glial cells in the CNS during development, homeostasis, and disease. Starting from embryonic development, the blood brain barrier (BBB) and its functions in health and disease are governed by close interactions between endothelial cells, astrocytes, and microglia. Thus, in the first review, Prat and coworkers highlight the importance of glial cells for the formation and regulation of the BBB, which establishes the anatomic and functional basis for the immunoprivileged status of the CNS. Brendecke and Prinz discuss the diversity of CNS resident, adjoining and infiltrating myeloid cells during inflammation. As Bguardians of the CNS^, microglia, the resident macrophage population in the CNS, as well as strategically located myeloid cell subsets in the meninges, the perivascular space and the choroid plexus provide immune surveillance and shape the inflammatory response within and at the borders of the CNS. Gold and El-Khoury review the role of microglia and the inflammasome in Alzheimer’s disease (AD) and outline immunologic aspects of this neurodegenerative disorder. Indeed, this work highlights the dichotomous role of microglia, which alternates between protective clearance of β-amyloid and detrimental neurotoxic effects evoked by the activation of the NLRP3 inflammasome by β-amyloid. These mechanisms provide a new aspect on the role of microglia during the pathogenesis of AD. Shemer and Jung focus on the role of resident microglia and infiltrating monocytes in CNS autoimmune diseases and emphasize therapeutic options targeting functional differences between these populations: infiltrating monocytes are critical for the effector phase of autoimmune CNS inflammation and actively initiate demyelination; however, microglia activation is required for monocyte recruitment to the CNS and precedes immune cell infiltration. These observations support therapeutic interventions targeting either microglial activation or monocyte recruitment for the treatment of inflammatory diseases. Rothhammer and Quintana discuss the role of astrocytes as an integral part of the blood brain barrier and a functionally heterogeneous CNS resident population. During autoimmune inflammatory processes, astrocytes are exposed to a plethora of cytokines and chemokines that modulate their response. In addition, astrocytes participate actively in the fine-tuning of the local inflammatory milieu. This review gives an overview of the most recent understanding about cytokine networks operational in astrocytes during autoimmune CNS inflammation and highlights potential targets for immunomodulatory therapies for multiple sclerosis (MS). Finally, Healy, Michell-Robinson, and Antel give an overview of the effects of current disease-modifying therapies for MS on the regulation of human glia. Based on their ability to cross the BBB, different drugs act on astrocytes, microglia, This article is a contribution to the Special Issue on : Role of Astrocytes and Microglia in CNS Inflammation Guest Editor: Francisco Quintana

Do not judge a cell by its cover--diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation.

Specialized populations of tissue-resident myeloid cells inhabit every organ of the body. While many of these populations appear similar morphologically and phenotypically, they exhibit great functional diversity. The central nervous system (CNS), as an immune privileged organ, possesses a unique tissue-resident macrophage population, the microglia, as well as numerous myeloid cell subsets at its boarders and barriers in CNS-adjoining tissues, namely the meninges, the perivascular space, and the choroid plexus. Recent research has added much to our knowledge about microglia, whereas the populations of CNS-surrounding phagocytes are just starting to be appreciated. As guardians of CNS homeostasis, these myeloid cells perform immune surveillance and immune modulatory tasks in health and disease. As such, microglia and CNS-surrounding antigen-presenting cells have been shown to be crucially involved not only in the initiation and progression but also resolution of multiple sclerosis (MS). MS and its rodent model, experimental autoimmune encephalomyelitis, are autoimmune inflammatory demyelinating CNS pathologies. While some crucial aspects of the disease pathogenesis have been solved, much of the complex involvement and interplay of the innate immune compartment remains yet to be clarified. Here, we will discuss the current understanding of the scope of phenotypes and functions of myeloid cells involved in CNS neuroinflammation.

IL-9 signaling affects central nervous system resident cells during inflammatory stimuli

Interleukin (IL) 9, a dominant cytokine in Th9 cells, has been proven to play a pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by augmenting T cell activation and differentiation; however, whether IL-9 signaling affects central nervous system (CNS)-resident cells during CNS autoimmunity remains unknown. In the present study, we found that the IL-9 receptor (IL-9R) was highly expressed in astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes and microglia cells, and that its expression was significantly upregulated in brain and spinal cord during EAE. In addition, IL-9 increased chemokine expression, including CXCL9, CCL20 and MMP3, in primary astrocytes. Although IL-9 had no effect on the proliferation of microglia cells, it decreased OPC proliferation and differentiation when in combination with other pro-inflammatory cytokines, but not with IFN-γ. IL-9 plus IFN-γ promoted OPC proliferation and differentiation. These findings indicate that CNS-restricted IL-9 signaling may be involved in the pathogenesis of MS/EAE, thus providing a potential therapeutic target for future MS/EAE treatment through disruption of CNS cell-specific IL-9 signaling.

Role of adaptor protein MyD88 in TLR-mediated preconditioning and neuroprotection after acute excitotoxicity.

Excitotoxic cell death is a crucial mechanism through which neurodegeneration occurs in numerous pathologies of the central nervous system (CNS), such as Alzheimer's disease, stroke and spinal cord injury. Toll-like receptors (TLRs) are strongly expressed on microglial cells and are key regulators of the innate immune response to neuronal damage. However, it is still unclear whether their stimulation is protective or harmful in excitotoxic contexts. In this study, we demonstrate that systemic administration of lipopolysaccharide (LPS) or Pam3CSK4 24h prior to an intrastriatal injection of kainic acid (KA) significantly protected cortical neurons in the acute phase of injury. Protection could not be detected with the TLR3 ligand poly-IC. Histological analyses revealed that microglia of LPS and Pam3CSK4 pre-conditioned group were primed to react to injury and exhibited a stronger expression of Tnf and Tlr2 mRNA. We also found that mice deficient for MyD88, a critical adaptor protein for most TLR, were more vulnerable than WT mice to KA-induced excitotoxicity at early (12h and 24h) and late (10days) time points. Finally, bone-marrow chimeric mice revealed that MyD88 signaling in CNS resident cells, but not in cells of hematopoietic origin, mediates the protective effect. This study unravels the potential of TLR2 and TLR4 agonists to induce a protective state of preconditioning against KA-mediated excitotoxicity and further highlights the beneficial role of cerebral MyD88 signaling in this context.

Direct and indirect effects of immune and central nervous system-resident cells on human oligodendrocyte progenitor cell differentiation.

In multiple sclerosis, successful remyelination within the injured CNS is largely dependent on the survival and differentiation of oligodendrocyte progenitor cells. During inflammatory injury, oligodendrocytes and oligodendrocyte progenitor cells within lesion sites are exposed to secreted products derived from both infiltrating immune cell subsets and CNS-resident cells. Such products may be considered either proinflammatory or anti-inflammatory and have the potential to contribute to both injury and repair processes. Within the CNS, astrocytes also contribute significantly to oligodendrocyte biology during development and following inflammatory injury. The overall objective of the current study was to determine how functionally distinct proinflammatory and anti-inflammatory human immune cell subsets, implicated in multiple sclerosis, can directly and/or indirectly (via astrocytes) impact human oligodendrocyte progenitor cell survival and differentiation. Proinflammatory T cell (Th1/Th17) and M1-polarized myeloid cell supernatants had a direct cytotoxic effect on human A2B5(+) neural progenitors, resulting in decreased O4(+) and GalC(+) oligodendrocyte lineage cells. Astrocyte-conditioned media collected from astrocytes pre-exposed to the same proinflammatory supernatants also resulted in decreased oligodendrocyte progenitor cell differentiation without an apparent increase in cell death and was mediated through astrocyte-derived CXCL10, yet this decrease in differentiation was not observed in the more differentiated oligodendrocytes. Th2 and M2 macrophage or microglia supernatants had neither a direct nor an indirect impact on oligodendrocyte progenitor cell differentiation. We conclude that proinflammatory immune cell responses can directly and indirectly (through astrocytes) impact the fate of immature oligodendrocyte-lineage cells, with oligodendrocyte progenitor cells more vulnerable to injury compared with mature oligodendrocytes.

Lymphocytic choriomeningitis and alpha-chemokines.

IP-10 and its receptor CXCR3 play an important role in lymphocytic choriomeningitis (LCM). During the course of LCM in mice not only cells of the immune system but also central nervous system (CNS) resident cells are actively involved in both the pro- and the counter-inflammatory immune circuits. A central role for IP-10 in regulating the accumulation of effector T cells at sites of CNS inflammation, with no apparent compensatory effect of other CXCR3 ligands, has been shown. The producers of IP-10 are mainly resident cells of the CNS, and astrocytes are the dominant expressors in the neural parenchyma, not microglial cells or recruited bone marrow-derived cell types. These results are consistent with a mode suggesting a bidirectional interplay between resident cells of the CNS and the recruited virus-specific T cells with astrocytes as active participants in the local antiviral host response.

Suppressors of cytokine signaling 1 and 3 are upregulated in brain resident cells in response to virus-induced inflammation of the central nervous system via at least two distinctive pathways.

Suppressors of cytokine signaling (SOCS) proteins are intracellular proteins that inhibit cytokine signaling in a variety of cell types. A number of viral infections have been associated with SOCS upregulation; however, not much is known about the mechanisms regulating SOCS expression during viral infection. In this study, we used two pathologically distinct intracerebral (i.c.) infection models to characterize temporal and spatial aspects of SOCS expression in the virus-infected central nervous system (CNS), and by employing various knockout mouse models, we sought to identify regulatory mechanisms that may underlie a virus induced upregulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual upregulation of SOCS1/3 mRNA expression peaking at day 7 postinfection (p.i.). In the LCMV model, SOCS mRNA was expressed in brain resident cells, including astrocytes and some neurons, and for SOCS1 in particular this upregulation was almost entirely mediated by gamma interferon (IFN-γ) produced by infiltrating T cells. After infection with YF, we also found SOCS expression to be upregulated in brain resident cells with a peak on day 7 p.i., but in this model, the upregulation was only partially dependent on IFN-γ and T cells, indicating that at least one other mediator was involved in the upregulation of SOCS following YF infection. We conclude that virus-induced inflammation of the CNS is associated with upregulation of SOCS1/3 mRNA expression in brain resident cells and that at least two distinctive pathways can lead to this upregulation. In the present report, we have studied the induction of SOCS1 and SOCS3 expression in the context of virus-induced CNS infection. We found that both a noncytolytic and a cytolytic virus induce marked upregulation of SOCS1 and -3 expression. Notably, the kinetics of the observed upregulation follows that of activity within proinflammatory signaling pathways and, interestingly, type II interferon (IFN), which is also a key inducer of inflammatory mediators, seems to be essential in initiating this counterinflammatory response. Another key observation is that not only cells of the immune system but also CNS resident cells are actively involved in both the pro- and the counterinflammatory immune circuits; thus, for example, astrocytes upregulate both C-X-C-motif chemokine 10 (CXCL10) and SOCS when exposed to type II IFN in vivo.

Is Central Nervous System an Immune-Privileged Site?

The central nervous system (CNS) was once considered to be an immune-privileged area. However, increasing evidence shows that the central nervous system is not an immune-privileged but is an active surveillance site. There is a bi-directional communication between the central nervous system and immune system. Normally, immune cells migrate into the central nervous system microenvironment through choroid plexus and interact with the central nervous system resident cells through either through neuromediators or immunomediators. This finding has led to a significant interest in neuroimmunological interactions and investigation onto the role of the immune system in the pathology of various neurological disorders and examine whether it can be targeted to produce novel therapeutic strategies.

Effect of the innate immune response on development of Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Theiler's murine encephalomyelitis virus (TMEV) infection of susceptible mice leads to the development of demyelinating disease in the central nervous system (CNS) associated with an inflammatory immune response. The demyelinating disease in mice has similarities to multiple sclerosis in humans and is used as an experimental model for the human disease. The innate immune response initiates the immune response to TMEV through innate immune receptors on cells that recognize components of the virus and activate intracellular signaling that leads to the expression of innate immune cytokines, chemokines, and effector molecules. The innate immune response directly affects the development of the adaptive immune response, especially the T cell response, which mediates viral clearance. However, infection of Swiss Jim Laboratory (SJL) mice with TMEV leads to a persistent virus infection of the microglia/macrophage in the CNS which contributes to the development of demyelinating disease. Susceptibility to demyelinating disease has been linked to the T cell response against the virus. However, the current studies will examine the role of the innate immune response to TMEV and the affect it has on the adaptive immune response and development of demyelinating disease following TMEV infection. The innate immune cytokines, chemokines, and effector molecules as well as the innate immune cells, both CNS resident and infiltrating peripheral cells, all contribute to the innate immune response following TMEV and may affect susceptibility to demyelinating disease.

Astrocytes produce IL-19 in response to bacterial challenge and are sensitive to the immunosuppressive effects of this IL-10 family member

There is growing appreciation that resident glial cells can initiate and/or regulate inflammation following trauma or infection in the central nervous system (CNS). We have previously demonstrated the ability of microglia and astrocytes to respond to bacterial pathogens or their products by rapid production of inflammatory mediators, followed by the production of the immunosuppressive cytokine interleukin (IL)−10. IL-19, another member of the IL-10 family of cytokines, has been studied in the context of a number of inflammatory conditions in the periphery and is known to modulate immune cell activity. In the present study, we demonstrate the constitutive and/or inducible expression of IL-19 and its cognate receptor subunits, IL-19Rα and IL-19Rβ (also known as IL-20R1 and IL-20R2, and IL-20RA and IL-20RB), in mouse brain tissue, and by primary murine and human astrocytes. We also provide evidence for the presence of a novel truncated IL-19Rα transcript variant in mouse brain tissue, but not glial cells, that shows reduced expression following bacterial infection. Importantly, IL-19R functionality in glia is indicated by the ability of IL-19 to regulate signaling component expression in these cells. Furthermore, while IL-19 itself had no effect on glial cytokine production, IL-19 treatment of bacterially infected or Toll-like receptor ligand stimulated astrocytes significantly attenuated pro-inflammatory cytokine production. The bacterially induced production of IL-19 by these resident CNS cells, the constitutive expression of its cognate receptor subunits, and the immunomodulatory effects of this cytokine, suggest a novel mechanism by which astrocytes can regulate CNS inflammation.

Molecule of the month: miRNA and Multiple Sclerosis.

Great strides are being made in our understanding of the large sea of non-coding RNAs that are found within eukaryotic cells. Regulation of gene expression in cells is subject to microRNA (miRNA) in normal and neuropsychiatric diseases [1, 2]. Here we discuss the involvement of miRNAs in the neurological disease, Multiple Sclerosis (MS). Many physicians and scientists have worked on the problem of MS with a goal to find a cure since Jean-Martin Charcot discovered and characterized MS. We briefly mention a few researchers here who contributed to this field. Today, many years after Charcot, although the cause of MS has not been identified, MS has been shown to involve major immune-related mechanistic components. These mechanisms of pathogenesis comprise processes that occur within the brain so that the brain tissue itself including myelin sheath-producing oligodendrocyte cells become targets. Specifically, MS, characterized by axonal damage, demyelination, and chronic inflammation, is considered a central nervous system (CNS) autoimmune disease. There is a long-standing paradigm that MS is a neurodegenerative disease associated with defects in the blood-brain barrier (BBB) as well as immunological mechanisms. Furthermore, molecular genetics and gene expression studies have widened the scope and understanding of the risk and mechanisms of MS pathogenesis. In addition to contributions of immunological studies, putative viruses have been associated with MS and viral and viral-immunological hypotheses have been addressed over time. Wallace W. Tourtellotte greatly contributed to the utilization of laboratory methods for the diagnosis of MS as well as possible viral factors and immunological mechanisms of pathogenesis [3–10]. Several aspects of MS pathogenesis involve miRNAs. In myeloid cells in MS, expression of miRNA, mir-155, is increased. Regulation by mir-155 of adaptive immune response and CNS resident and blood-derived myeloid cells occurs in MS [11]. In MS, BBB dysfunction is pathognomic with MS pathogenesis. Consistent with this, miRNA miR-125a-5p is a component of regulation of immune cell efflux and tightness of endothelial cells in brain [12]. In brain, miR-124 was increased in hippocampi from MS patients and demyelination was increased in these areas. Neuronal gene expression (mRNA) was decreased for 26 proteins including ionotrophic glutamate receptors AMPA2 and AMPA3. In a mouse model, similar results were found and these changes were reversed by remyelination [13]. In astrocytes from brain tissue of active MS plaque lesions, ten miRNAs were upregulated including miRNA-155, miRNA-34a, and miRNA-326. The mRNA for protein CD47 (that inhibits macrophage phagocytosis of myelin) was correspondingly decreased. This implies that macrophages are thereby released from inhibition and this process is associated with demyelination under these conditions in MS active plaque lesions [14]. In MS, miRNAs show tissue specificity. However, there are similar profiles among different tissues. In blood and in active MS lesions/plaques, miR-326 is upregulated. However, miR-323 is not upregulated in serum but is upregulated in T-reg cells, active brain lesions/plaques, and whole blood [15]. Conceivably, dysregulation of gene expression in hematopoietic cells could be caused by altered miRNA expression. Twenty-two miRNAs involved in immunity were studied in peripheral blood mononuclear cells (PBMCs) of healthy controls vs. MS patients. Only three miRNAs showed increased expression and none showed decreased expression. Mir-155 was most upregulated. A three-SNP haplotype was identified that should be studied further; mir-155 is derived from a region involving B-cell Integration Cluster non-coding RNA (BIC) and is located at band q21.3 on chromosome 21 [3, 16]. In conclusion, an analytic technique for analysis of several miRNA databases developed methods to integrate their information related to MS. Results indicated differences among blood and brain tissue from MS patients. Sixteen miRNAs were associated with MS. MiRNA-mRNA prediction studies indicated 1,498 possible target genes in a network. Five hundred genes, each, were predicted as central hubs for hsa-miR-20b-5p and hsa-miR-20a-5p. Transcription factor activity, T cell activation, and signaling accounted for many of the target genes. Thus, miRNAs behave in a super-stratum of regulators of gene expression regulation in MS [17].

IFNγ Influences Type I Interferon Response and Susceptibility to Theiler's Virus-Induced Demyelinating Disease

Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible SJL mice that has similarities to multiple sclerosis in humans. TMEV infection of susceptible mice leads to a persistent virus infection of the central nervous system (CNS), which promotes the development of demyelinating disease associated with an inflammatory immune response in the CNS. TMEV infection of resistant C57BL6 mice results in viral clearance without development of demyelinating disease. Interestingly, TMEV infection of resistant mice deficient in IFNγ leads to a persistent virus infection in the CNS and development of demyelinating disease. We have previously shown that the innate immune response affects development of TMEV- induced demyelinating disease, thus we wanted to determine the role of IFNγ during the innate immune response. TMEV-infected IFNγ-deficient mice had an altered innate immune response, including reduced expression of innate immune cytokines, especially type I interferons. Administration of type I interferons, IFNα and IFNß, to TMEV-infected IFNγ-deficient mice during the innate immune response restored the expression of innate immune cytokines. Most importantly, administration of type I interferons to IFNγ-deficient mice during the innate immune response decreased the virus load in the CNS and decreased development of demyelinating disease. Microglia are the CNS resident immune cells that express innate immune receptors. In TMEV-infected IFNγ-deficient mice, microglia had reduced expression of innate immune cytokines, and administration of type I interferons to these mice restored the innate immune response by microglia. In the absence of IFNγ, microglia from TMEV-infected mice had reduced expression of some innate immune receptors and signaling molecules, especially IRF1. These results suggest that IFNγ plays an important role in the innate immune response to TMEV by enhancing the expression of innate immune cytokines, especially type I interferons, which directly affects the development of demyelinating disease.

The art of forging neurons: direct reprogramming of somatic cells into induced neuronal cells

Abstract Cellular reprogramming has shed new light on the plasticity of terminally differentiated cells and unearthed novel strategies for cell-based therapies to treat neurological disor­ders. With accumulating knowledge of the programs underlying the genesis of the dis­tinct neural cell types, particularly the iden­tification of crucial transcription factors and microRNAs, reprogramming of somatic cells of different origins into induced neuronal cells or neural stem cells has been success­fully achieved. Starting with the general con­cept of reprogramming, we discuss three dif­ferent paradigms: (1) direct conversion of central nervous system (CNS) foreign cells such as skin fibroblasts into induced neuro­nal cells or neural stem cells; (2) transdiffer­entiation of CNS resident cells such as astro­cytes and brain pericytes into induced neuro­nal cells; (3) reprogramming of one neuronal subtype into another. The latter has already been successfully achieved in vivo during ear­ly brain development, providing a strong im­pulse to attempt direct reprogramming in si­tu for future brain repair.

Vitamin D reduces development and progression of virus-induced demyelinating disease (P5131)

Abstract Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that is associated with an inflammatory immune response. Microglia are the CNS resident immune cells which have been shown to be activated during MS. Virus infections have been suggested as a causative agent for MS, and vitamin D insufficiency has been correlated with disease development. Thus, we wanted to determine whether higher vitamin D levels at the time of virus infection could alter development of demyelinating disease. Theiler’s murine encephalomyelitis virus (TMEV) induced demyelinating disease is an animal model of MS. TMEV infection of susceptible mice leads to development of a demyelinating disease associated with an inflammatory immune response in the CNS. Our studies showed that increased levels of vitamin D3 at the time of virus infection reduced development and progression of demyelinating disease. Vitamin D reduced the number of CD4+ T cells expressing IFNγ and increased the number of CD25+CD4+ T cells. Most interestingly, vitamin D reduced the expression of pro-inflammatory cytokines and increased the expression of IL-10 and type I interferons by microglia. The reduction in the inflammatory immune response by microglia was dependent on IL-10 induction of SOCS3. Overall, these results show that vitamin D reduced the inflammatory immune response in the CNS and reduced the development and progression of demyelinating disease following virus infection.

Fibronectin aggregation in multiple sclerosis lesions impairs remyelination

Remyelination following central nervous system demyelination is essential to prevent axon degeneration. However, remyelination ultimately fails in demyelinating diseases such as multiple sclerosis. This failure of remyelination is likely mediated by many factors, including changes in the extracellular signalling environment. Here, we examined the expression of the extracellular matrix molecule fibronectin on demyelinating injury and how this affects remyelination by oligodendrocytes progenitors. In toxin-induced lesions undergoing efficient remyelination, fibronectin expression was transiently increased within demyelinated areas and declined as remyelination proceeded. Fibronectin levels increased both by leakage from the blood circulation and by production from central nervous system resident cells. In chronically demyelinated multiple sclerosis lesions, fibronectin expression persisted in the form of aggregates, which may render fibronectin resistant to degradation. Aggregation of fibronectin was similarly observed at the relapse phase of chronic experimental autoimmune encephalitis, but not on toxin-induced demyelination, suggesting that fibronectin aggregation is mediated by inflammation-induced demyelination. Indeed, the inflammatory mediator lipopolysaccharide induced fibronectin aggregation by astrocytes. Most intriguingly, injection of astrocyte-derived fibronectin aggregates in toxin-induced demyelinated lesions inhibited oligodendrocyte differentiation and remyelination, and fibronectin aggregates are barely expressed in remyelinated multiple sclerosis lesions. Therefore, these findings suggest that fibronectin aggregates within multiple sclerosis lesions contribute to remyelination failure. Hence, the inhibitory signals induced by fibronectin aggregates or factors that affect fibronectin aggregation could be potential therapeutic targets for promoting remyelination.

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-α and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-α than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

In vivo dynamics of innate immune sentinels in the CNS

The innate immune system is comprised of cellular sentinels that often serve as the first responders to injury and invading pathogens. Our basic understanding of innate immunity is derived from research conducted in peripheral lymphoid tissues. However, it is now recognized that most non-lymphoid tissues throughout the body are equipped with specialized innate immune cells that are uniquely adapted to the niches in which they reside. The central nervous system (CNS) is a particularly interesting compartment because it contains a population of post-mitotic cells (neurons) that are intolerant of robust, cytopathic inflammatory responses observed in many peripheral tissues. Thus, evolutionary adaptations have fitted the CNS with a unique array of innate immune sentinels that facilitate the development of local inflammatory responses but attempt to do so in a manner that preserves the integrity of its post-mitotic residents. Interestingly, studies have even suggested that CNS resident innate immune cells contribute to the homeostasis of this compartment and promote neural activity. In this review we discuss recent advances in our understanding of CNS innate immune sentinels and how novel imaging approaches such as intravital two-photon laser scanning microscopy (TPLSM) have shed light on these cells during states of health and disease.

Cytotoxic effect of IL-17A on neural stem cells as a mechanism underlying Th17-cell-induced proinflammatory demyelination (59.7)

Abstract IL-17A, a Th17 cell-derived proinflammatory molecule, has been found to play an important role in the pathogenesis of autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The IL-17A receptor (IL-17RA), through which IL-17A signals, is expressed in many immune-related cells, including central nervous system resident cells such as microglia and astrocytes. However, whether IL-17A exerts a direct effect on neural stem cells (NSCs) and oligodendrocytes, thus inducing inflammatory demyelination in the central nervous system is not known. Here we report that IL-17RA is constitutively expressed on NSCs, oligodendrocytes and their precursors. IL-17A significantly reduced NSC proliferation, which was mainly due to cytotoxicity, but not to induction of apoptosis. IL-17A did not influence the differentiation of NSCs into neural cells. The effects of IL-17A are similar to those of TNF-α, another proinflammatory cytokine that plays a pathogenic role in EAE; however, a synergistic/additive effect of these two molecules has not been observed. We conclude that IL-17RA is expressed in NSCs, through which IL-17A blocks proliferation of these cells, resulting in reduced numbers of myelinating cells such as oligodendrocytes and their precursors. Thus, in addition to its proinflammatory role in the immune system, IL-17A also plays a direct role in inducing demyelination and blocking neuronal repair in EAE/MS.

Toll-Like Receptor Signaling in Alzheimer?s Disease Progression

Evidence continues to underpin the role of the innate immune system in pathologies associated with neuroinflammation. Neuroinflammation is the complex innate immune response of neural tissue to control infection, and Toll-like receptors (TLRs), a major family of pattern recognition receptors (PRRs) that mediate innate immunity, have emerged as players in Alzheimer’s disease (AD). Upon ligation with their ligand, TLRs induce signaling involving recruitment of various adaptors and signaling molecules that culminate in the activation of genes including interferons and cytokines. TLR expression has been identified on resident central nervous system cells including microglia and neurons, with an altered expression profile for this receptor determined in microglia from AD patients. Furthermore, TLR activation on microglia is associated with amyloid-β (Aβ) clearance from the brain, suggesting that modulation of TLR signaling may be a therapeutic strategy for plaque removal. This review will highlight evidence linking the TLR system with the progression of AD, assessing TLR involvement in events associated with AD in cellular systems, transgenic murine models of AD and in humans.