Loss of astrocytic leptin signaling worsens experimental autoimmune encephalomyelitis

Leptin is commonly thought to play a detrimental role in exacerbating experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Paradoxically, we show here that astrocytic leptin signaling has beneficial effects in reducing disease severity. In the astrocyte specific leptin receptor knockout (ALKO) mouse in which leptin signaling is absent in astrocytes, there were higher EAE scores (more locomotor deficits) than in the wildtype counterparts. The difference mainly occurred at a late stage of EAE when wildtype mice showed signs of recovery whereas ALKO mice continued to deteriorate. The more severe symptoms in ALKO mice coincided with more infiltrating cells in the spinal cord and perivascular brain parenchyma, more demyelination, more infiltrating CD4 cells, and a lower percent of neutrophils in the spinal cord 28 days after EAE induction. Cultured astrocytes from wildtype mice showed increased adenosine release in response to interleukin-6 and the hippocampus of wildtype mice had increased adenosine production 28 days after EAE induction, but the ALKO mutation abolished the increase in both conditions. This indicates a role of astrocytic leptin in normal gliotransmitter release and astrocyte functions. The worsening of EAE in the ALKO mice in the late stage suggests that astrocytic leptin signaling helps to clear infiltrating leukocytes and reduce autoimmune destruction of the CNS.     

Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well‐established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6?/?) mice. Compared with Klk6+/+ (wild‐type) mice, Klk6?/? mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease‐9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood–brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors. Scanning electron microscopic analysis revealed demyelination characterized by myelin detachment from the axons in the early phase of EAE progression (days 3–7) in Klk6+/+ mice but not in Klk6?/? mice. Interestingly, anti‐MOG (myelin oligodendrocyte glycoprotein) autoantibody was also detected in the cerebrospinal fluid (CSF) and spinal cord on day 3 after MOG immunization. Furthermore, treatment of primary cultured OLs with anti‐MOG autoantibody induced oligodendroglial morphological changes and increases in myelin basic protein and Klk6 expression. We also developed a novel enzyme‐linked immunoabsorbent assay method for detecting activated KLK6 in human CSF. In human autopsy brain samples, expression of active KLK6 was detected in OLs using an antibody that specifically recognizes the protein's activated form. Taken together, our findings demonstrate that Klk6 secreted by OLs plays a critical role in the pathogenesis of EAE/MS and that it might serve as a potential therapeutic target for MS.     

Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system (CNS). EAE pathogenesis involves various cell types, cytokines, chemokines, and adhesion molecules. Given the complexity of the inflammatory response in EAE, it is likely that many immune mediators still remain to be discovered. To identify novel immune mediators of EAE pathogenesis, we performed an Affymetrix gene array screen on the spinal cords of mice at the onset stage of disease. This screening identified the gene encoding lipocalin 2 (Lcn2) as being significantly upregulated. Lcn2 is a multi-functional protein that plays a role in glial activation, matrix metalloproteinase (MMP) stabilization, and cellular iron flux. As many of these processes have been implicated in EAE, we characterized the expression and role of Lcn2 in this disease in C57BL/6 mice. We show that Lcn2 is significantly upregulated in the spinal cord throughout EAE and is expressed predominantly by monocytes and reactive astrocytes. The Lcn2 receptor, 24p3R, is also expressed on monocytes, macrophages/microglia, and astrocytes in EAE. In addition, we show that EAE severity is increased in Lcn2(-/-) mice as compared with wild-type controls. Finally, we demonstrate that elevated levels of Lcn2 are detected in the plasma and cerebrospinal fluid (CSF) in MS and in immune cells in CNS lesions in MS tissue sections. These data indicate that Lcn2 is a modulator of EAE pathogenesis and suggest that it may also play a role in MS.     

Deficient p75 low-affinity neurotrophin receptor expression does alter the composition of cellular infiltrate in experimental autoimmune encephalomyelitis in C57BL/6 mice

We have shown earlier that induction of experimental autoimmune encephalomyelitis (EAE)-a model for the human disease multiple sclerosis-in C57BL/6 wild-type mice resulted in the expression of the p75 low-affinity neurotrophin receptor (p75NTR) in endothelial cells in the CNS. In comparison to the clinical manifestation of EAE observed in wild-type C57BL/6 mice, C57BL/6 mice deficient for p75NTR (p75NTR knockout mice) developed a more severe or even lethal disease and concomitant increased levels of inflammation in the CNS. In order to elucidate the role of endothelial p75NTR in cellular infiltration under these pathological circumstances, we have performed a more detailed, quantitative examination of the composition of the cellular infiltrate invading the CNS in EAE wild-type and EAE p75NTR knockout mice. We compared spinal cords of EAE wild-type with those of EAE p75NTR knockout mice of the same clinical score (3.5) using immunohistochemical markers for the cell types present in the infiltratory cuffs in EAE: T-cells, B-cells, monocytes, microglia, resident and infiltrating macrophages and polymorphonuclear cells. Interestingly, we detected that the proportion of B-cells, cells of the monocyte-macrophage lineage and polymorphonuclear cells in the infiltratory cuff of EAE-p75NTR knockout mice was decreased at the account of the proportion of T-cells which appeared to be almost doubled in comparison to the EAE wild-type mice. The altered composition of the infiltrate in p75NTR deficient mice argues for an involvement of endothelial p75NTR in the interaction between the inflamed endothelium and the activated cells of the immune system, in particular the T-cells, in EAE.     

Expression of osteopontin and its ligand, CD44, in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis

The expression of osteopontin (OPN) and one of its ligands, CD44, was studied in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE). Western blot analysis showed that osteopontin significantly increased at the early and peak stage of EAE and slightly declined thereafter. Osteopontin was constitutively expressed in some astrocytes adjacent to pia mater and neurons in normal rats, and was shown to be increased in the same cells and also in some inflammatory cells including macrophages at the early and peak stage of EAE. CD44, a ligand for osteopontin, was constitutively expressed in astrocytes in normal and control spinal cords and was also expressed in inflammatory cells, as well as increased expression in astrocytes in EAE. These findings suggest that inflammatory cells as well as reactive astrocytes are major sources of osteopontin in rat EAE, and osteopontin may interact with its ligand CD44 on astrocytes and inflammatory cells in EAE, possibly mediating autoimmune central nervous system (CNS) diseases in rats.     

Saturable Leptin Transport Across the BBB Persists in EAE Mice

We have shown that mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, have upregulated leptin receptor expression in reactive astrocytes of the hippocampus, a region involved in sickness behavior. Leptin can exacerbate EAE when its serum concentration is high. Although leptin receptors in astrocytes modulate leptin transport across cultured endothelial cell monolayers, it is not known how leptin transport in EAE mice is regulated. Here, we determined brain and cervical spinal cord uptake of leptin in early and recovery stages of EAE, after either intravenous delivery or in situ brain perfusion of ¹²⁵I-leptin and the vascular marker ¹³¹I-albumin. While increased vascular space and general blood–brain barrier (BBB) permeability after EAE were expected, the specific saturable transport system for leptin crossing the BBB also persisted. Moreover, there was upregulation of leptin transport in hippocampus and cervical spinal cord in the early stage of EAE, shown by higher leptin uptake in these regions and by competitive inhibition with coadministered excess unlabeled leptin. We conclude that EAE induced a time- and region-specific increase of leptin transport. The results provide a link between circulating leptin and enhanced leptin signaling that may play a crucial role in disease progression.     

Upregulation of water channel aquaporin-4 in experimental autoimmune encephalomyeritis

Aquaporin-4 (AQP4) is a water channel protein that plays an important role in water movement in the central nervous system (CNS). Recently, presence of anti-AQP4 antibody has been reported in the sera from patients with neuromyelitis optica. AQP4 is therefore a possible target for inflammatory mechanisms in CNS. In the present investigation, we performed semi-quantitative analysis of AQP4-mRNA in brain and spinal cord from mice affected with experimental autoimmune encephalomyelitis (EAE) using real-time PCR. AQP4-mRNA expression was increased in EAE; reaching a peak in the spinal cord at 14 days, and in the brain at 21 days after first inoculation. Immunohistochemical analysis showed that AQP4 is expressed on astrocytes, indicating that the increase in AQP4 expression may correlate with astrocytic activation. This is the first study to demonstrate upregulation of AQP4 in EAE. The upregulation of AQP4 could be involved in the development of inflammation in the acute phase of EAE.     

Expression of citrullinated proteins in murine experimental autoimmune encephalomyelitis

In this study, we demonstrate for the first time the immunohistochemical expression of citrullinated proteins in the central nervous system (CNS) of mice with myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). By using an established monoclonal antibody (F95) against natural and synthetic citrullinated proteins (Nicholas and Whitaker [2002] Glia 37:328-336), numerous, small, previously unrecognized "patches" of citrullinated proteins were discovered throughout EAE brains, whereas EAE spinal cords showed similar but much larger lesions. On dual color immunofluorescence, these lesions were found to contain citrullinated myelin basic protein (MBP) and were surrounded by astrocytes immunoreactive for both glial fibrillary acidic protein (GFAP) and F95. These lesions became evident about the time when EAE mice became symptomatic and increased in size and number with increasing disease severity. In some sections of spinal cord but not brains of severely debilitated EAE mice, a widespread gliotic response was seen, with astrocytes containing citrullinated GFAP spread throughout the gray and white matter. Western blot analysis of acidic proteins from the brains and spinal cords of EAE mice had higher levels of multiple citrullinated GFAP isoforms compared with controls, with more F95-positive bands in the EAE brains vs. spinal cords. These results raise the possibility that citrullination of both GFAP and MBP may contribute to the pathophysiology of EAE and that the brains of EAE mice may contain more pathology than previously realized.     

趋化因子MCP-1、MIP-1α在EAE小鼠脊髓中的表达

目的:研究单核细胞趋化蛋白(MCP)-1和巨噬细胞炎性蛋白(MIP)-1α与实验性自身免疫性脑脊髓炎(EAE)发病的关系。方法:用髓鞘少突胶质细胞糖蛋白_(35-55)多肽加福氏完全佐剂皮下注射免疫C57BL/6小鼠建立EAE模型,用免疫组织化学方法观察EAE小鼠发病后第0天(初期)、第7天(高峰期)及第30天(恢复期)脊髓中MCP-1、MIP-1α的表达的变化,并通过免疫组化染色标记星形胶质细胞及小胶质细胞,判断MCP-1、MIP-1α的细胞来源。结果: MCP-1、MIP-1α在EAE小鼠发病初期脊髓中有少量表达,发病高峰期表达增高,而恢复期无表达,MCP-1主要由星形胶质细胞产生,MIP-1α主要由小胶质细胞产生;对照组小鼠脊髓中则没有MCP-1、MIP-1α表达。结论:趋化因子MCP-1、MIP-1α在EAE小鼠CNS不同胶质细胞中表达,是EAE发病早期募集免疫反应细胞向CNS浸润的重要致炎性因子。     

Chemokine expression in GKO mice (lacking interferon-gamma) with experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) considered to be an animal model for multiple sclerosis (MS). The detailed mechanism that specifies accumulation of inflammatory cells within the CNS in these conditions remains a subject of active investigation. Chemokines including IP-10, GRO-alpha, MCP-1 are produced in EAE tissues selectively by parenchymal astrocytes, but the regulatory stimuli that govern this expression remain undetermined. The unexpected occurrence of increased EAE susceptibility in Balb/c GKO mice (lacking IFN-gamma) offered an opportunity to examine the spectrum of chemokine expression during immune-mediated inflammation in the absence of a single regulatory cytokine. We found that chemokines MCP-1 and GRO-alpha were upregulated in the CNS of mice with EAE despite the GKO genotype. IP-10, which is highly expressed in the CNS of mice with an intact IFN-gamma gene and EAE, was strikingly absent. In vitro experiments confirmed that IFNgamma selectively stimulates astrocytes for IP-10 expression. These results indicate that IP-10 is dependent upon IFN-gamma for its upregulation during this model disease, and document directly that astrocyte expression of chemokines during EAE is governed by pro-inflammatory cytokines.     

Endothelial NOS‐deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a demyelinating autoimmune disease characterized by infiltration of T cells into the central nervous system (CNS) after compromise of the blood‐brain barrier. A model used to mimic the disease in mice is experimental autoimmune encephalomyelitis (EAE). In this report, we examine the clinical and histopathological course of EAE in eNOS‐deficient (eNOS^?/?) mice to determine the role of nitric oxide (NO) derived from this enzyme in the disease progression. We find that eNOS^?/? mice exhibit a delayed onset of EAE that correlates with delayed BBB breakdown, thus suggesting that NO production by eNOS underlies the T cell infiltration into the CNS. However, the eNOS^?/? mice also eventually exhibit more severe EAE and delayed recovery, indicating that NO undertakes dual roles in MS/EAE, one proinflammatory that triggers disease onset, and the other neuroprotective that promotes recovery from disease exacerbation events. © 2009 Wiley‐Liss, Inc.     

Effector and suppressor roles for LFA-1 during the development of experimental autoimmune encephalomyelitis

LFA-1 (CD11a/CD18) is a member of the β₂-integrin family of adhesion molecules important in leukocyte trafficking and activation. Although LFA-1 is thought to contribute to the development of experimental autoimmune encephalomyelitis (EAE) primarily through its functions on effector T cells, its importance on other leukocyte populations remains unexplored. To address this question, we performed both adoptive transfer EAE experiments involving CD11a^?/? mice and trafficking studies using bioluminescent T cells expressing luciferase under the control of a CD2 promoter (T-lux cells). Transfer of encephalitogenic CD11a^?/? T cells to wild type mice resulted in a significant reduction in overall EAE severity compared to control transfers. We also observed, using in vivo imaging techniques, that CD11a^?/? T-lux cells readily infiltrated lymph nodes and the CNS of wild type recipients with kinetics comparable to CD11a^+/+ transfers, although their overall numbers in these organs were reduced. Surprisingly, transfer of encephalitogenic wild type T cells to CD11a^?/? mice induced a severe and sometimes fatal EAE disease course, associated with massive T cell infiltration and proliferation in the CNS. These data indicate that LFA-1 expression on leukocytes in recipient mice plays an important immunomodulatory role in EAE. Thus, LFA-1 acts as a key regulatory adhesion molecule during the development of EAE, serving both pro- and anti-inflammatory roles in disease pathogenesis.     

Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease

Reactive astrocytosis, involving activation, hypertrophy, and proliferation of astrocytes, is a characteristic response to inflammation or injury of the central nervous system. We have investigated whether inhibition of reactive astrocytosis influences established experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We made use of transgenic mice, which express herpes simplex virus-derived thymidine kinase under control of a glial fibrillary acidic protein promotor (GFAP HSV-TK mice). Treatment of these mice with ganciclovir leads to inhibition of reactive astrocytosis. When GFAP HSV-TK mice were treated for seven days following onset of EAE with ganciclovir, disease severity increased. Although aquaporin-4 staining on astrocyte endfeet at the glia limitans remained equally detectable, GFAP immunoreactivity and mRNA expression in CNS were reduced by this treatment. Ganciclovir-treated GFAP HSV-TK mice with EAE had a 78% increase in the total number of infiltrating myeloid cells (mainly macrophages), whereas we did not find an increase in infiltrating T cells, using quantitative flow cytometry. Per cell expression of mRNA for the macrophage-associated molecules TNFα, MMP-12 and TIMP-1 was elevated in spinal cord of GFAP HSV-TK mice treated with ganciclovir. Relative expression of CD3ε was downregulated, and expression levels of IFNγ, IL-4, IL-10, IL-17, and Foxp3 were not significantly changed. mRNA expression of CCL2 was upregulated, and CXL10 was downregulated. Thus, inhibition of reactive astrocytosis after initiation of EAE leads to increased macrophage, but not T cell, infiltration, and enhanced severity of EAE. This emphasizes the role of astrocytes in controlling leukocyte infiltration in neuroinflammation.     

Characterization of relapsing–remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Like MS, the animal model experimental autoimmune encephalomyelitis (EAE) is characterized by CNS inflammation and demyelination and can follow a relapsing–remitting (RR) or chronic (CH) disease course. The molecular and pathological differences that underlie these different forms of EAE are not fully understood. We have compared the differences in RR‐ and CH‐EAE generated in the same mouse strain (C57BL/6) using the same antigen. At the peak of disease when mice in both groups have similar clinical scores, CH‐EAE is associated with increased lesion burden, myelin loss, axonal damage, and chemokine/cytokine expression when compared with RR‐EAE. We further showed that inflammation and myelin loss continue to worsen in later stages of CH‐EAE, whereas these features are largely resolved at the equivalent stage in RR‐EAE. Additionally, axonal loss at these later stages is more severe in CH‐EAE than in RR‐EAE. We also demonstrated that CH‐EAE is associated with a greater predominance of CD8⁺ T cells in the CNS that exhibit MOG_35–55 antigen specificity. These studies therefore showed that, as early as the peak stage of disease, RR‐ and CH‐EAE differ remarkably in their immune cell profile, chemokine/cytokine responses, and histopathological features. These data also indicated that this model of CH‐EAE exhibits pathological features of a chronic‐progressive disease profile and suggested that the sustained chronic phenotype is due to a combination of axonal loss, myelin loss, and continuing inflammation. © 2009 Wiley‐Liss, Inc.     

Fas system up-regulation in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated disorder characterized by infiltration of the central nervous system (CNS) by mononuclear cells and macrophages, and serves as a model for multiple sclerosis. In acute monophasic and relapsing remitting forms of EAE, the CNS inflammatory infiltrates are cleared within a few days and, simultaneously, animals recover from their clinical disability. The mechanisms for rapid disappearance of the inflammatory cells are not fully understood. Fas and Fas-ligand (Fas-L) molecules are thought to play an important role in the deletion of autoimmune reactive T cells through apoptosis. However, recent observations in transgenic lpr and gld mice show that mutations inactivating Fas and Fas-L respectively ameliorate signs of EAE despite persistence of immune cell infiltrates into the CNS. In the current study, the expression of Fas and Fas-L was investigated by immunochemistry and in situ hybridization during the course of EAE in DA rats that were actively immunized with syngenic spinal cord homogenate. CNS apoptotic cells were simultaneously examined using terminal transferase dUTP nick end-labeling techniques. During the acute phase of the disease, a significant proportion of CNS CD4+ cells (80%) and macrophages (50%) expressed Fas and Fas-L (80 and 60%, respectively). Simultaneously, about 20% of CD4+ cells and 30% of macrophages were found to be apoptotic. Some astrocytes and neurons also expressed Fas and Fas-L, although they did not appear to be apoptotic. These results further support a role for Fas-mediated lymphocyte and macrophage apoptosis in this model of CNS autoimmune disease but they also suggest a more complex role for Fas/Fas-L interactions in CNS autoimmunity, including resident cells.     

An Apparent Correlation Between Central Nervous System and Kidney’s Erythropoietin and TNF Alpha Expression at Peak Experimental Autoimmune Encephalomyelitis Disease

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelination disease associated with inflammatory reactions and attenuation of antioxidant capacity. Several lines of evidence show that organs such as the liver and kidneys can share their antioxidant activity to protect the central nervous system (CNS) against neurodegenerative diseases. The aim of this study was to examine the possible interplay of the kidneys and CNS in pathogenesis of EAE. For this purpose, EAE model was induced in C57BL/6 mice, and expression of erythropoietin (EPO), TNF-α, and NFκB-1 was determined in the kidney and CNS at early and peak stages of the disease. Besides, changes in serum level of EPO and total antioxidant capacity (TAC) were measured by different clinical scores. Real-time PCR (qPCR) results showed a substantial increase in TNF-α and NFκB-1 expression in mice at EAE peak stage compared to sham (control). There was a positive correlation between kidney-EPO and CNS-inflammatory factor expression in EAE-induced mice. In general, EPO expression was relatively higher in the kidneys compared to CNS tissue in sham group. There was a significant upregulation in expression of EPO in the brain, spinal cord, and kidneys particularly at peak stage. Accordingly, changes in serum TAC were consistent with serum EPO concentration. This data may suggest that there is an EPO-mediated cross-talk between the kidney and CNS during EAE pathogenesis.     

Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, resulting in accumulated loss of cognitive, sensory, and motor function. This study evaluates the neuropathological effects of voluntary exercise in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Two groups of C57BL/6J mice were injected with an emulsion containing myelin oligodendrocyte glycoprotein and then randomized to housing with a running wheel or a locked wheel. Exercising EAE mice exhibited a less severe neurological disease score and later onset of disease compared with sedentary EAE animals. Immune cell infiltration and demyelination in the ventral white matter tracts of the lumbar spinal cord were significantly reduced in the EAE exercise group compared with sedentary EAE animals. Neurofilament immunolabeling in the ventral pyramidal and extrapyramidal motor tracts displayed a more random distribution of axons and an apparent loss of smaller diameter axons, with a greater loss of fluorescence immunolabeling in the sedentary EAE animals. In lamina IX gray matter regions of the lumbar spinal cord, sedentary animals with EAE displayed a greater loss of α‐motor neurons compared with EAE animals exposed to exercise. These findings provide evidence that voluntary exercise results in reduced and attenuated disability, reductions in autoimmune cell infiltration, and preservation of axons and motor neurons in the lumbar spinal cord of mice with EAE. © 2014 Wiley Periodicals, Inc.     

RON-regulated innate immunity is protective in an animal model of multiple sclerosis

The tyrosine kinase receptor RON and its ligand, macrophage stimulating protein (MSP), exert inhibitory effects on systemic innate immunity, but their CNS expression and impact on human neuroinflammatory diseases are unknown were RON and MSP present in human brain perivascular macrophages and microglia, but RON mRNA and protein abundance in the CNS were diminished in both MS patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE). Treatment of differentiated human monocytoid cells with MSP resulted in significant reduction of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and MMP-9 mRNA levels, whereas minimal effects were observed in human astrocytes. After induction of EAE, RON knockout and heterozygote animals exhibited significantly increased CNS proinflammatory gene (TNF-alpha, MMP-12) expression compared with wild-type littermate controls, although IL-4 levels were suppressed in both RON-deficient groups. Neurological disease in RON-deficient animals showed a more rapid onset with overall worsened severity, together with exacerbated demyelination, axonal injury, and neuroinflammation after EAE induction. The proto-oncogene, c-Cbl, which modulates ubiquitylation of RON, was increased in glia in both MS brains and EAE spinal cords. Thus, the MSP-RON pathway represents a novel regulatory mechanism within the CNS by which innate immunity and its pathogenic effects could be targeted for future therapeutic interventions.