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Sci. Signal., 22 May 2012
Vol. 5, Issue 225, p. ra38
[DOI: 10.1126/scisignal.2002767]


Interferon-β Therapy Against EAE Is Effective Only When Development of the Disease Depends on the NLRP3 Inflammasome

Makoto Inoue1, Kristi L. Williams2, Timothy Oliver3*, Peter Vandenabeele4,5, Jayant V. Rajan6,7, Edward A. Miao8, and Mari L. Shinohara1,9{dagger}

1 Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
2 Departments of Medicine and Cardiology, Duke University Medical Center, Durham, NC 27710, USA.
3 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
4 Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie (VIB), 9052 Ghent (Zwijnaarde), Belgium.
5 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent (Zwijnaarde), Belgium.
6 Institute for Systems Biology, Seattle, WA 98103, USA.
7 Department of Medicine, University of Washington, Seattle, WA 98195, USA.
8 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
9 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.

* Deceased.

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.

{dagger} To whom correspondence should be addressed. E-mail: mari.shinohara{at}

Citation: M. Inoue, K. L. Williams, T. Oliver, P. Vandenabeele, J. V. Rajan, E. A. Miao, M. L. Shinohara, Interferon-β Therapy Against EAE Is Effective Only When Development of the Disease Depends on the NLRP3 Inflammasome. Sci. Signal. 5, ra38 (2012).

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