Susceptible Mouse Strains Research Articles

ELR(+) chemokine signaling in host defense and disease in a viral model of central nervous system disease.

Intracranial infection of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis, accompanied by viral replication in glial cells and robust infiltration of virus-specific T cells that contribute to host defense through cytokine secretion and cytolytic activity. Mice surviving the acute stage of disease develop an immune-mediated demyelinating disease, characterized by viral persistence in white matter tracts and a chronic neuroinflammatory response dominated by T cells and macrophages. Chemokines and their corresponding chemokine receptors are dynamically expressed throughout viral infection of the CNS, influencing neuroinflammation by regulating immune cell infltration and glial biology. This review is focused upon the pleiotropic chemokine receptor CXCR2 and its effects upon neutrophils and oligodendrocytes during JHMV infection and a number of other models of CNS inflammation.

AB0175 C1Q Regulates the TLR7-Mediated Inflammatory Response by Pristane-Primed Macrophages: Implications for Pristane-Induced Lupus (PIL)

BackgroundIntraperitoneal injection of the natural oil pristane induces loss of immune tolerance and development of pristane-induced lupus (PIL) in susceptible mouse strains. PIL is characterised by high titres of autoantibodies,...

C5a/C5aR pathway is essential for the pathogenesis of murine viral fulminant hepatitis by way of potentiating Fgl2/fibroleukin expression

Viral fulminant hepatitis (FH) remains a serious clinical problem with very high mortality. Lacking understanding of FH pathogenesis has in essence hindered efficient clinical treatment. Inferring from a correlation observed between the genetic differences in the complement component 5 (C5) and the susceptibility of mouse strains to murine hepatitis virus strain-3 (MHV-3) infections, we propose that excessive complement activation plays a critical role in the development of FH. We show that MHV-3 infection causes massive complement activation, along with a rapid increase in serum C5a levels and quick development of FH in susceptible strains. Mice deficient in the C5a receptor (C5aR) or the susceptible strains treated with C5aR antagonists (C5aRa) exhibit significant attenuation of the disease, accompanied by a remarkable reduction of hepatic fibrinogen-like protein 2 (Fgl2), a hallmark protein that causes necrosis of infected livers. In accordance, biopsy of FH patients shows a dramatic increase of Fgl2 expression, which correlates with C5aR up-regulation in the liver. In vitro C5a administration accelerates MHV-3-induced Fgl2 secretion by macrophages. Furthermore, inhibiting ERK1/2 and p38 efficiently blocks C5a-mediated Fgl2 production during viral infections. These data provide evidence that mouse susceptibility to MHV-3-induced FH may rely on C5a/C5aR interactions, for which ERK1/2 and p38 pathways participate in up-regulating Fgl2 expression. Inhibition of C5a/C5aR interactions is expected to be beneficial in the clinical treatment of FH patients.

Helicobacter hepaticus cholesterol-α-glucosyltransferase is essential for establishing colonization in male A/JCr mice.

Helicobacter pylori cholesterol-α-glucosyltransferase (cgt) is essential for survival of H. pylori in mice. Enterohepatic H. hepaticus, the cause of colonic and hepatocellular carcinoma in susceptible mouse strains, contains an ortholog of the H. pylori cgt. However, the role of cgt in the pathogenesis of H. hepaticus has not been investigated. Two cgt-deficient isogenic mutants of wild-type H. hepaticus (WT) 3B1 were generated and used to inoculate male A/JCr mice. Cecal and hepatic colonization levels of the mutants and WT 3B1 as well as select inflammation-associated cytokines were measured by qPCR at 4 months postinoculation. Both mutants were undetectable in the cecum of any inoculated mice (10 per mutant) but were detected in two livers (one for each mutant); by contrast, 9 and 7 of 10 mice inoculated with WT 3B1 were qPCR positive in the ceca and livers, respectively. The mice inoculated with the mutants developed significantly less severe hepatic inflammation (p < .05) and also produced significantly lower hepatic mRNA levels of proinflammatory cytokines Ifn-γ (p < .01) and Tnf-α (p ≤ .02) as well as anti-inflammatory factors Il10 and Foxp3 compared with the WT 3B1-inoculated mice. Additionally, the WT 3B1-inoculated mice developed significantly higher Th1-associated IgG2a (p < .0001) and Th2-associated IgG1 responses (p < .0001) to H. hepaticus infection than mice dosed with isogenic cgt mutants. Our data indicate that the cholesterol-α-glucosyltransferase is required for establishing colonization of the intestine and liver and therefore plays a critical role in the pathogenesis of H. hepaticus.

Enhanced anti-retroviral cytotoxic T cell response by PD-1 blockade (VIR4P.1015)

Abstract LP-BM5 retrovirus induces a complex disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS) in susceptible strains of mice, such as C57BL/6 (B6). Our lab has previously shown that a cytotoxicT lymphocyte (CTL) response to MAIDS-associated epitopes that are shared by MAIDS-associated terminal B-cell lymphomas can be detected in uninfected, MAIDS-associated tumor cell primed B6 mice. We further confirmed that B6 mice infected with LP-BM5 retrovirus can generate equally robust anti-MAIDS tumor CTLs compared to the B6 mice primed with tumor cells. To determine if the anti-tumor CD8 T-cell responses can be enhanced by interrupting the down-regulatory PD-1 pathway specifically in the CD8 T-cell compartment, thus to treat MAIDS-associated B-cell lymphomas, we determined whether adoptive transfer of PD-1KO CD8 T cells with or without total CD4 T cells, was able to protect Rag-1KO mice from B6-1710 tumor challenge. Rag-1KO recipients that received B6.PD-1KO.CD8 T cells showed delayed tumor growth following B6-1710 tumor challenge compared to Rag-1KO mice that received equal numbers of w.t B6.CD8 T cells. This enhanced anti-tumor activity was similar to what was observed in mice that received combined PD-1 blockade in CD8 T cell compartment and depletion of CD4 T regulatory cells. Our data indicate that anti-tumor CD8 T cell response can be increased by interrupting the down-regulatory, CD8 T-cell mediated PD-1 pathway.

Differential regulation of T cell responses and disease severity by mycoplasma and its superantigen in autoimmune diabetic mouse (BA15P.228)

Abstract Infection has been extensively documented as a serious problem causing high mortality and morbidity in diabetic populations. M. arthritidis produces a potent superantigen (SAg) MAM, which has been shown to be at least partially responsible for the septic shock induced in certain susceptible mouse strains. In the present study, we have investigated how diabetic immune cells respond to the M. arthritidis and MAM SAg. By using two well-defined animal models of diabetes, STZ and NOD mice, we found that STZ mice infected with M. arthritidis developped severe lethal toxicity and the immune cells predominantly produces pro-inflammatory cytokines TNFalpha, IL-6, IL-1β, chemokines CCR2/4 and Tbx21, a Th1-related transcription factor; while MAM-activated T cells from NOD mice display a mixture of Th1 and Th17 profiles which are associated with the elevated levels of ICOS molecule and a unique transcription factor LSF (tcfcp2). Since ERK, a signaling protein of MAPK family, is reported to be responsible for the phosphorylation of LSF in T cell activation, thus we propose a novel ERK-LSF-ICOS signaling cascade that is required for the Th1/Th17 development in NOD mice in response to MAM. Our findings further suggest that the inhibition of these molecules might be potentially therapeutic in the alleviation of mortality and morbidity in diabetic individuals with severe infections.

Anti-viral effects of CGRP in mixed glial cells infected with LP-BM5 virus (VIR5P.1022)

Abstract LP-BM5 retrovirus infection is an established murine model used to study HIV infection in humans due to that susceptible strains of mice (including C57BL/6(B6) mice) develop immunodeficiency syndrome (termed as MAIDS) following LP-BM5 infection. Previously, we observed that calcitonin gene related protein (CGRP), a neuropeptide produced primarily by sensory neurons, reduced LP-BM5 viral loads in infected mixed glial cells (primarily astrocytes and microglia). The mechanism through which CGRP decreases the viral loads is still not known. To elucidate the role of CGRP in glial LP-BM5 infection, we first determined that CGRP did not induce an increased cell death post-infection or directly decrease the viral infectivity. Then, we investigated whether CGRP could affect viral infectivity by enhancing the glycosylation of the cell receptor for viral attachment, murine cationic amino acid transporter 1 (mCAT-1). Our data indicate that blocking glycosylation by Tunicamycin did not affect CGRP’s anti-viral effects. Further, we tested the involvement of p38 MAPK pathway in CGRP-induced inhibitory effects. Preliminary experiment using a p38 inhibitor, SB203580, suggests a p38 mediated mechanism. Future studies will further elucidate the role of p38 and examine the role of other CGRP downstream pathways on LPBM5 infection.

Anti-TRIM21 autoantibody and inflammasome interaction in pathogenesis of Sjogren's syndrome (BA3P.200)

Abstract Sjögren’s syndrome is a chronic autoimmune disorder mainly affecting the exocrine glands and is commonly associated with autoantibodies to TRIM21. This study was undertaken to determine the role of TRIM21-reactive antibodies in pathogenesis of Sjögren’s syndrome. NZM mouse strains (2758, 2328, 2410) were immunized with recombinant TRIM21 protein adsorbed on to alum. Mice were monitored for autoantibodies, serum cytokines and pilocarpine induced salivation. Although all NZM mouse strains generated a robust anti-TRIM21 antibody response, salivary gland dysfunction only occurred in the NZM2758 mice. Moreover, alum immunized NZM2758 mice also displayed some loss of glandular function. Serum levels of IL-1α and CXCL1 were upregulated in alum and alum-TRIM21 treated groups of NZM2758 mice. In contrast, levels of IL-2, IL-5, IL-6 and IL-17 were upregulated, only in the alum-TRIM21 treated mice. Antibodies from TRIM21 immunized mice penetrated live cells in vitro, and showed cytoplasmic staining. Passive transfer of sera from TRIM21 immunized mice induced salivary gland dysfunction in recipient mice, only if the recipients were pre primed with alum. Our study shows that in a genetically susceptible mouse strain, anti-TRIM21 antibodies directly affected salivary gland function and this phenomenon was dependent on the activation of inflammasome pathway. Thus, interaction between innate and adaptive immunity is critical for pathogenesis of Sjögren’s syndrome.

Investigation of the Cytotoxic, Genotoxic, and Apoptosis-Inducing Effects of Estragole Isolated from Fennel (Foeniculum vulgare)

The present study was undertaken to evaluate, in the HepG2 human hepatoma cell line, the in vitro cytotoxic, genotoxic, and apoptotic activities of estragole (1), contained in the essential oil of Foeniculum vulgare (fennel) and suspected to induce hepatic tumors in susceptible strains of mice. Toward this end, an MTT cytotoxicity assay, a trypan blue dye exclusion test, a double-staining (acridine orange and DAPI) fluorescence viability assay, a single-cell microgel-electrophoresis (comet) assay, a mitochondrial membrane potential (Δψm) assay, and a DNA fragmentation analysis were conducted. In terms of potential genotoxic effects, the comet assay indicated that estragole (1) was not able to induce DNA damage nor apoptosis under the experimental conditions used.

Pulmonary endothelial injury in the context of perturbed transforming growth factor β signalling as a unique model of pulmonary hypertension in scleroderma

BackgroundThe development of pulmonary arterial hypertension in scleroderma remains an important contributor to mortality in this condition, despite substantial improvements in outcomes due to modern therapeutic strategies. No animal models of scleroderma develop this important complication. We describe the constitutive vascular phenotype of a mouse model of scleroderma and show that pulmonary endothelial injury replicates the pathological changes of pulmonary arterial hypertension seen in human disease. MethodsThe TβRIIΔk-fib mouse strain expresses a kinase-deficient type II transforming growth factor β (TGFβ) receptor driven by a fibroblast-specific promoter leading to ligand-dependent upregulation of TGFβ signalling; this mouse strain replicates key fibrotic features of scleroderma. We did structural, biochemical, and functional assessments of pulmonary and systemic vessels, including in-vivo haemodynamic studies, before and after vascular endothelial growth factor receptor (VEGFR) inhibition with SU5416, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGFβ, endothelin, and VEGF signalling axes in vivo; tissue sections; and explanted pulmonary arterial smooth muscle cells. FindingsIn the TβRIIΔk-fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly raised pulmonary artery pressures resemble the well-described chronic hypoxia model of pulmonary hypertension. After administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis-resistant proliferating endothelial cells; the result was right ventricular hypertrophy confirming haemodynamically significant pulmonary arterial hypertension. Altered TGFβ, endothelin, and ligand and receptor expression of VEGF were consistent with a scleroderma phenotype. InterpretationThis study replicates key features of scleroderma-associated pulmonary arterial hypertension in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support functional interplay between TGFβ, endothelin, and VEGF that provides insight into pathogenesis. FundingArthritis Research UK.

The TIM-3 pathway ameliorates Theiler’s murine encephalomyelitis virus-induced demyelinating disease

Infection by Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. T-cell immunoglobulin and mucin domain-3 (TIM-3) has been demonstrated to play a crucial role in the maintenance of peripheral tolerance. In this study, we examined the regulatory role of the TIM-3 pathway in the development of TMEV-induced demyelinating disease (TMEV-IDD). The expression of TIM-3 was increased at both protein and mRNA levels in the spinal cords of mice with TMEV-IDD compared with naive controls. In addition, by utilizing a blocking mAb, we demonstrate that TIM-3 negatively regulates TMEV-specific ex vivo production of IFN-γ and IL-10 by CD4(+) T cells and IFN-γ by CD8(+) T cells from the CNS of mice with TMEV-IDD at 36 days post-infection (dpi). In vivo blockade of TIM-3 by using the anti-TIM-3 mAb resulted in significant exacerbation of the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells in the CNS was also increased in mice administered with anti-TIM-3 mAb both at the induction phase (10 dpi) and at the effector phase (36 dpi). Flow cytometric analysis of intracellular cytokines revealed that the number of CD4(+) T cells producing TNF, IL-4, IL-10 and IL-17 was significantly increased at the effector phase in the CNS of anti-TIM-3 mAb-treated mice. These results suggest that the TIM-3 pathway plays a critical role in the regulation of TMEV-IDD.

Therapeutic application of mesenchymal stromal cells in murine models of inflammatory bowel disease.

Mesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory bowel disease (IBD), including Crohn's disease. The models of colitis induced by intrarectal infusion of 2,4,6-trinitrobenzene sulfonic acid (TNBS) or by oral administration of dextran sulfate sodium (DSS) in susceptible mouse strains have been commonly used as preclinical tools to demonstrate the efficiency of treatments with MSCs isolated from various sources. Both models are being and will be critical to improve MSC-based therapies in human IBD by assaying new pathways, therapeutic regimes and tissue targeting strategies. Here, we describe our experiences in the treatment of acute and chronic TNBS- and DSS-induced colitis with MSCs.

Effect of Amphotericin B Nanodisks on Leishmania major Infected Mice.

ObjectiveTo assess the efficacy of a novel formulation of the polyene antibiotic, amphotericin B (AMB), as therapy for cutaneous leishmaniasis in different mouse strains.Methods(AMB), was formulated into water-soluble transport particles, termed nanodisks (ND). Balb/c and CH3 mice infected with Leishmania major on Day 0 were administered vehicle alone, empty ND or AMB-ND on Day 1 and day 7, via the tail vein. Mice were sacrificed 25 or 50 days post inoculation and tissue histology evaluated. Balb/c mice treated with vehicle or empty ND showed signs of severe infection while CH3 mice had less inflammation and fewer parasites. AMB-ND treatment (2 mg/kg) had a marked therapeutic effect on L. major infected Balb/c mice and a discernable therapeutic benefit on CH3 mice.ConclusionsAMB-ND is efficacious in the treatment of cutaneous leishmaniasis in both susceptible and resistant mouse strains. It may be inferred that AMB-ND may be useful for prophylactic and/or treatment of early stage Leishmania spp. infection.

Regulatory lymphocytes are key factors in MHC-independent resistance to EAE.

Background and Objectives. Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE), an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods. For EAE induction, female C57BL/6 (susceptible strain) and CD1 (resistant outbred strain showing heterogeneous MHC antigens) mice were immunized with the 35–55 peptide of myelin oligodendrocyte glycoprotein (MOG35−55). We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results. Upon immunization with MOG35−55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35−55. Accordingly, resistant mice experienced a rise in regulatory B cells (P = 0.001) and, to a lower extent, in regulatory T cells (P = 0.02) compared with C57BL/6 susceptible mice. As a consequence, MOG35−55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P = 0.02) and IL-17 (P = 0.009) and higher serum levels of IL-17 (P = 0.04) than resistant mice. Conclusions. Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism.

Prioritizing genes responsible for host resistance to influenza using network approaches

BackgroundThe genetic make-up of humans and other mammals (such as mice) affects their resistance to influenza virus infection. Considering the complexity and moral issues associated with experiments on human subjects, we have only acquired partial knowledge regarding the underlying molecular mechanisms. Although influenza resistance in inbred mice has been mapped to several quantitative trait loci (QTLs), which have greatly narrowed down the search for host resistance genes, only few underlying genes have been identified.ResultsTo prioritize a list of promising candidates for future functional investigation, we applied network-based approaches to leverage the information of known resistance genes and the expression profiles contrasting susceptible and resistant mouse strains. The significance of top-ranked genes was supported by different lines of evidence from independent genetic associations, QTL studies, RNA interference (RNAi) screenings, and gene expression analysis. Further data mining on the prioritized genes revealed the functions of two pathways mediated by tumor necrosis factor (TNF): apoptosis and TNF receptor-2 signaling pathways. We suggested that the delicate balance between TNF’s pro-survival and apoptotic effects may affect hosts’ conditions after influenza virus infection.ConclusionsThis study considerably cuts down the list of candidate genes responsible for host resistance to influenza and proposed novel pathways and mechanisms. Our study also demonstrated the efficacy of network-based methods in prioritizing genes for complex traits.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-14-816) contains supplementary material, which is available to authorized users.

Elimination of Friend Retrovirus in the Absence of CD8+T Cells

Friend retrovirus complex (FV) induces acute erythroid cell hyperplasia and massive splenomegaly followed by the emergence of fatal erythroleukemia upon inoculation into adult mice of susceptible strains ([1][1][–][2][3][3]). Because the disease can progress in the presence of host immune

Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension.

To delineate the constitutive pulmonary vascular phenotype of the TβRIIΔk-fib mouse model of scleroderma, and to selectively induce pulmonary endothelial cell injury using vascular endothelial growth factor (VEGF) inhibition to develop a model with features characteristic of pulmonary arterial hypertension (PAH). The TβRIIΔk-fib mouse strain expresses a kinase-deficient transforming growth factor β (TGFβ) receptor type II driven by a fibroblast-specific promoter, leading to ligand-dependent up-regulation of TGFβ signaling, and replicates key fibrotic features of scleroderma. Structural, biochemical, and functional assessments of pulmonary vessels, including in vivo hemodynamic studies, were performed before and following VEGF inhibition, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGFβ and VEGF signaling axes in tissue sections and explanted smooth muscle cells. In the TβRIIΔk-fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly elevated pulmonary artery pressure resembled the well-described chronic hypoxia model of pulmonary hypertension. Following administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis-resistant proliferating endothelial cells. These changes resulted in right ventricular hypertrophy, confirming hemodynamically significant PAH. Altered expression of TGFβ and VEGF ligand and receptor was consistent with a scleroderma phenotype. In this study, we replicated key features of systemic sclerosis-related PAH in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support the underlying role of functional interplay between TGFβ and VEGF, which provides insight into the pathogenesis of this disease.

Quantitative immunophenotypic analysis of antigen-presenting cells involved in ectromelia virus antigen presentation in BALB/c and C57BL/6 mice

During mousepox in resistant (C57BL/6) or susceptible (BALB/c) strains of mice, stimulation of Th1 or Th2 cytokine immune response, respectively, is observed. Because mechanisms of different polarization of T cells remain elusive, in this study, we quantitatively assessed the phenotype of antigen-presenting cells (APCs) involved in ectromelia virus (ECTV) antigen presentation and cluster formation with effector cells in secondary lymphoid organs of BALB/c and C57BL/6 mice. We showed that both strains of mice display similar dynamics and kinetics of viral antigen presentation by CD11c(+) , CD11b(+) , and CD19(+) cells. CD11c(+) and CD11b(+) cells highly participated in viral antigen presentation during all stages of mousepox, whereas CD19(+) cells presented viral peptides later in infection. The main population of dendritic cells (DCs) engaged in ECTV antigen presentation and cell junction formation with effector cells was a population of myeloid CD11b(+) DCs (mDCs). We suggest that, on the one hand, ECTV may differentially affect the functions of APCs depending on the strain of mice. On the other hand, we suggest that some types of APCs, such as mDCs or other DCs subsets, have different abilities to direct the shape of immune response depending on the host resistance to mousepox.

Cross‐presentation of malaria antigen by brain microvessels: why CD8+ T cells are critical for the pathogenesis of experimental cerebral malaria

Cross‐presentation of malaria antigen by brain microvessels: why <scp>CD</scp>8⁺ T cells are critical for the pathogenesis of experimental cerebral malaria

Upregulation of voltage-gated Ca2+ channels in mouse astrocytes infected with Theiler’s murine encephalomyelitis virus (TMEV)

Theiler’s murine encephalomyelitis virus (TMEV) induces demyelination in susceptible strains of mice through a CD4+ Th1 T cell-mediated immunopathological process. TMEV infection produces a syndrome in mice that resembles multiple sclerosis. In this work, we focused on the increased expression of the genes encoding voltage-gated Ca2+ channel subunits in SJL/J mouse astrocytes infected in culture with a BeAn strain of TMEV. Affymetrix DNA murine genome U74v2 DNA microarray hybridized with cRNA from mock- and TMEV-infected astrocytes revealed the upregulation of four sequences encoding Ca2+-binding and Ca2+ channel subunit proteins. The DNA hybridization results were further validated using conventional RT-PCR and quantitative RT-PCR, demonstrating the increased expression of mRNA encoding channel subunit proteins. Western blotting also showed the increased synthesis of L- and N-type channel subunit specific proteins after infection. The reduced expression and the functional upregulation of functional voltage-gated Ca2+ channels in mock- and TMEV-infected cells, respectively, was demonstrated using voltage clamp experiments. TMEV infection in mouse astrocytes induced a Ca2+ current with a density proportional to the amount of viral particles used for infection. The use of Ca2+ channel blockers, nimodipine and ω-conotoxin-GVIA, showed that both functional L- and N-type Ca2+ channels were upregulated in infected astrocytes. The upregulation of Ca2+ channels in astrocytes after TMEV infection provides insight into the molecular processes and potential role of astrocyte Ca2+ dysregulation in the pathophysiology of encephalomyelitis and is important for the development of novel therapeutic strategies leading to prevention of neurodegeneration.