The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice
Beichu Guo, Elmer Y. Chang, Genhong Cheng
Beichu Guo, Elmer Y. Chang, Genhong Cheng
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Research Article Autoimmunity

The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice

Abstract

IFN-β, 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-β–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-β–mediated IL-27 production by innate immune cells was critical for the immunoregulatory role of IFN-β in the CNS autoimmune disease. Together, our findings not only may provide a molecular mechanism for the clinical benefits of IFN-β 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.

Authors

Beichu Guo, Elmer Y. Chang, Genhong Cheng

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Figure 6

Type I IFN–mediated IL-27 production in macrophages contributes to inhibition of IL-17 production.

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Type I IFN–mediated IL-27 production in macrophages contributes to inhib...
(A) CM from IFN-β–treated macrophages suppresses Th17 development. WT, TRIF-deficient, and IFNAR-deficient BMMs were stimulated with IFN-β for 24 hours. Supernatants from IFN-β–stimulated macrophages were used as CM; they were added to Th17 culture and incubated for 72 hours. IL-17 production by CD4+ T cells was determined by ELISA. (B) WT and IFNAR-deficient BMMs were stimulated with IFN-β for 24 hours. The level of IL-27 protein was measured by ELISA. Data shown are representative of at least 3 experiments. (C) IFN-β–mediated inhibitory effects on Th17 development are reversed in the presence of anti–IL-27 antibody. CM from IFN-β–stimulated WT macrophages together with anti–IL-27 antibody or control IgG was added to Th17 cell culture. After 72 hours, IL-17 production by CD4+ T cells was determined by ELISA. (D) IL-27 contributes to IFN-β–mediated inhibition of encephalitogenic T cells. Lymphocytes isolated from immunized WT mice were restimulated with MOG peptide for 72 hours in the presence of CM from IFN-treated macrophages plus anti–IL-27 antibody or control IgG. IL-17 levels were measured by ELISA. (E) Lymphocytes isolated from immunized IFNAR–/– mice were restimulated with MOG peptide in the presence of CM from IFN-treated macrophages plus anti–IL-27 antibody. IL-27 treatment was included as a positive control. IL-17 level was measured after 72 hours of culture.