Abstract
Theiler´s murine encephalomyelitis virus (TMEV)-infection is a widely used animal model for studying demyelinating disorders, including multiple sclerosis (MS). The immunosuppressive cytokine Interleukin (IL)-10 counteracts hyperactive immune responses and critically controls immune homeostasis in infectious and autoimmune disorders. In order to investigate the effect of signaling via Interleukin-10 receptor (IL-10R) in infectious neurological diseases, TMEV-infected SJL mice were treated with IL-10R blocking antibody (Ab) in the acute and chronic phase of the disease. The findings demonstrate that (i) Ab-mediated IL-10 neutralization leads to progressive colitis with a reduction in Foxp3+ regulatory T cells and increased numbers of CD8+CD44+ memory T cells as well as activated CD4+CD69+ and CD8+CD69+ T cells in uninfected mice. (ii) Concurrent acute TMEV-infection worsened enteric disease-mediated by IL-10R neutralization. Virus-triggered effects were associated with an enhanced activation of CD4+ T helper cells and CD8+ cytotoxic T lymphocytes and augmented cytokine expression. By contrast, (iii) IL-10R neutralization during chronic TMEV-infection was not associated with enhanced peripheral immunopathology but an increased CD3+ T cell influx in the spinal cord. IL-10R neutralization causes a breakdown in peripheral immune tolerance in genetically predisposed mice, which leads to immune-mediated colitis, resembling inflammatory bowel disease. Hyperactive immune state following IL-10R blockade is enhanced by central nervous system-restricted viral infection in a disease phase-dependent manner.
Highlights
Theilers murine encephalomyelitis virus (TMEV)-infection is a widely used animal model for studying demyelinating disorders, including human multiple sclerosis (MS)
To characterize changes of the peripheral immune system associated with interleukin-10 receptor (IL-10R) deficiency-mediated colitis, phenotypical and cytokine expression analyses of spleen tissues were performed during the acute and chronic phase of Theiler’s murine encephalomyelitis (TME)
Interleukin-10 receptor blockade in SJL mice is accompanied by decreased levels of CD4+ forkhead box P3 (Foxp3)+ regulatory T cells together with enhanced CD44 and CD69 expression on T cells in the spleen
Summary
Theilers murine encephalomyelitis virus (TMEV)-infection is a widely used animal model for studying demyelinating disorders, including human multiple sclerosis (MS). Resistant C57BL/6 mice eliminate the virus from the central nervous system (CNS) by specific cellular immunity, including effector CD8+ cytotoxic T lymphocytes (CTL) responses during the acute infection phase [7]. The main functions of IL-10 include down-regulation of pro-inflammatory cytokine expression, reduction of antigen (Ag) presentation and reduced T cell activation [8,9,10,11,12,13,14]. The critical role of IL-10 in immune-mediated disorders is demonstrated in human inflammatory bowel disease (IBD), a chronic, relapsing, idiopathic inflammation of the intestinal tract. Genetic deficiency of either IL-10 or IL10R in transgenic mice leads to a breakdown in immune tolerance and immune mediated colitis, representing a well-established murine model for IBD [26,27,28]
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