The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice.
IFN-beta, a type I IFN, is widely used for the treatment of MS. However, the mechanisms behind its therapeutic efficacy are not well understood. Using a murine model of MS, EAE, we demonstrate that the Th17-mediated development of autoimmune disease is constrained by Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta-dependent (TRIF-dependent) type I IFN production and its downstream signaling pathway. Mice with defects in TRIF or type I IFN receptor (IFNAR) developed more severe EAE. Notably, these mice exhibited marked CNS inflammation, as manifested by increased IL-17 production. In addition, IFNAR-dependent signaling events were essential for negatively regulating Th17 development. Finally, IFN-beta-mediated IL-27 production by innate immune cells was critical for the immunoregulatory role of IFN-beta in the CNS autoimmune disease. Together, our findings not only may provide a molecular mechanism for the clinical benefits of IFN-beta in MS but also demonstrate a regulatory role for type I IFN induction and its downstream signaling pathways in limiting Th17 development and autoimmune inflammation.
Guo
Beichu
B
Department of Microbiology, Immunology, and Molecular Genetics, 8-240 Factor Building, University of California, 10833 Le Conte Avenue, Los Angeles, California 90095, USA.
Chang
Elmer Y
EY
Cheng
Genhong
G
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*
D033942:Adaptor Proteins, Vesicular Transport; D007370:Interferon Type I; D020381:Interleukin-17; D007378:Interleukins; D053633:Receptor, Interferon alpha-beta; C508032:Ifnar1 protein, mouse; C486767:Il27 protein, mouse; C476286:Ticam1 protein, mouse