Abstract
BackgroundExperimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells. The transcription factor interferon regulatory factor 3 (IRF3) is activated by pathogen recognition receptors and induces interferon-β production.MethodsTo determine the role of IRF3 in autoimmune inflammation, we immunised wild-type (WT) and irf3−/− mice to induce EAE. Splenocytes from WT and irf3−/− mice were also activated in vitro in Th17-polarising conditions.ResultsClinical signs of disease were significantly lower in mice lacking IRF3, with reduced Th1 and Th17 cells in the central nervous system. Peripheral T-cell responses were also diminished, including impaired proliferation and Th17 development in irf3−/− mice. Myelin-reactive CD4+ cells lacking IRF3 completely failed to transfer EAE in Th17-polarised models as did WT cells transferred into irf3−/− recipients. Furthermore, IRF3 deficiency in non-CD4+ cells conferred impairment of Th17 development in antigen-activated cultures.ConclusionThese data show that IRF3 plays a crucial role in development of Th17 responses and EAE and warrants investigation in human multiple sclerosis.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells
Myelin-reactive CD4+ T cells lacking interferon regulatory factor 3 (IRF3) completely failed to transfer EAE in an IL-23-driven, Th17-biased model, as did WT cells transferred into irf3−/− recipients
Deficiency of interferon regulatory factor 3 inhibits experimental autoimmune encephalomyelitis To investigate the role of IRF3 in central nervous system (CNS) autoimmune inflammation, we induced EAE in WT and irf3−/− mice with MOG35–55 in complete Freund’s adjuvant (CFA) medium
Summary
Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells. The transcription factor interferon regulatory factor 3 (IRF3) is activated by pathogen recognition receptors and induces interferon-β production. Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) [1]. Both MS and EAE are thought to be initiated by myelin-reactive CD4+ T cells that produce interferon-γ (IFN-γ) and interleukin-17 (IL-17) (that is, Th1 and Th17 cells, respectively) [2,3,4]. IRF3 activation is part of the first line of defence against invading viruses, and its activation results in the production of IFN-β IRF3 in the nucleus can activate the type I IFN promoters, the IFN-β promoter in particular
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