Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome

Makoto Inoue, Kristi L. Williams, Timothy Oliver, Peter Vandenabeele, Jayant V. Rajan, Edward A. Miao, Mari L. Shinohara

Research output: Contribution to journalArticlepeer-review

Abstract

Interferon-β (IFN-β) is widely used to treat multiple sclerosis (MS), and its efficacy was demonstrated in the setting of experimental autoimmune encephalomyelitis (EAE), an animal model of MS; however, IFN-β is not effective in treating all cases of MS. Here, we demonstrate that signaling by IFNAR (the shared receptor for IFN-α and IFN-β) on macrophages inhibits activation of Rac1 and the generation of reactive oxygen species (ROS) through suppressor of cytokine signaling 1 (SOCS1). The inhibition of Rac1 activation and ROS generation suppressed the activity of the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome, which resulted in attenuated EAE pathogenicity. We further found that two subsets of EAE could be defined on the basis of their dependency on the NLRP3 inflammasome and that IFN-β was not an effective therapy when EAE was induced in an NLRP3 inflammasome-independent fashion. Thus, our study demonstrates a previously uncharacterized signaling pathway that is involved in the suppression of EAE by IFN-β and characterizes NLRP3-independent EAE, which cannot be treated with IFN-β.

Original languageEnglish (US)
Article numberra38
JournalScience Signaling
Volume5
Issue number225
DOIs
StatePublished - May 22 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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