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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
Published April 1, 2008
Citation Information: J Clin Invest. 2008;118(5):1680-1690. https://doi.org/10.1172/JCI33342.
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Research Article Autoimmunity Article has an altmetric score of 3

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

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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 8

IL-27 reverses severe EAE phenotype in IFNAR–/– mice in vivo.

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IL-27 reverses severe EAE phenotype in IFNAR–/– mice in vivo.
   
(A) IL...
(A) IL-27 inhibits adoptive transfer of EAE in IFNAR–/– mice. Spleen and lymph node cells isolated from immunized IFNAR–/– mice were restimulated in vitro with MOG peptide in the presence of IL-27 or PBS for 72 hours. 3 × 107 cells were transferred into IFNAR–/– naive recipient mice via tail-vein injection (5 mice per group). (B) IFN-β–mediated IL-27 production inhibits adoptive transfer EAE in IFNAR–/– mice. Spleen and lymph node cells isolated from immunized IFNAR–/– mice were restimulated in vitro with MOG peptide in the presence of CM from IFN-treated macrophages with or without anti–IL-27 antibody. After 72 hours, 3 × 107 cells were transferred into naive IFNAR–/–recipient mice via tail-vein injection (5 mice per group). (C) IL-27 inhibits EAE development in WT mice. WT mice (n = 5) were immunized with MOG peptide emulsified in CFA. Recombinant carrier-free mouse IL-27 (0.25 μg in 100 μl PBS) was administered by s.c. injection to immunized WT mice every other day from day 2 until day 20. (D) Splenocytes from IL-27–treated WT mice represented in C were restimulated in vitro with MOG peptides for 72 hours, and IL-17 production was measured. (E) IL-27 treatment reverses the phenotype of EAE in IFNAR–/– mice. Recombinant mouse IL-27 was administered by s.c. injection to immunized IFNAR–/– mice (n = 5) every other day from day 2 until day 20. (F) Splenocytes from IL-27–treated IFNAR–/– mice represented in E were restimulated in vitro with MOG peptides for 72 hours, and IL-17 production was measured.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 10 patents
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