Research Article

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

Science Signaling22 May 2012Vol 5, Issue 225p. ra38DOI: 10.1126/scisignal.2002767

Inflammasome Dependency Determines Therapy?

Multiple sclerosis (MS) is an inflammatory autoimmune disease in which the myelin sheath surrounding axons is destroyed by cells of the immune system. MS and experimental autoimmune encephalitis (EAE), an animal model of MS, can be ameliorated by interferon-β (IFN-β); however, IFN-β is not effective in all cases. Inoue et al. determined a mechanism by which IFN-β decreases the severity of EAE in mice by inhibiting the activity of the NLRP3 inflammasome. However, the authors also characterized a form of EAE that was independent of NLRP3 and was refractory to IFN-β. Given other reports that have suggested the involvement of inflammasomes in MS, it will be important to investigate whether patients who fail to respond to IFN-β have inflammasome-independent disease.


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.

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Supplementary Material


Fig. S1. IFNAR signaling suppresses activation of the NLRP3 inflammasome.
Fig. S2. IFNAR signaling does not inhibit pro–IL-1β production.
Fig. S3. IFNAR signaling inhibits the formation of caspase-1 foci.
Fig. S4. IFNAR signaling does not affect expression of Nlrp3, Asc, Casp-1, and Txnip or the abundance of P2X7R and CD39, but does induce ROS generation.
Fig. S5. ROS generated by mitochondria, but not by NADPH oxidase, is suppressed by type I IFN.
Fig. S6. Inhibition of Rac1 inhibits the production of IL-1β and ROS, but does not affect the expression of Tnf, Il6, or Il1b.
Fig. S7. Involvement of SOCS1 in IFNAR signaling.
Fig. S8. Events upstream of the NLRP3 inflammasome are intact in NLRP3 inflammasome–deficient macrophages.
Fig. S9. Serum IL-18 concentrations 9 days after immunization.
Fig. S10. Evaluation of rIFN-β efficacy in cell culture.
Fig. S11. IFNAR signaling suppresses NLRP3 inflammasome activity in vivo.
Fig. S12. NLRP3 inflammasome–dependent and –independent EAE.
Fig. S13. Inflammasome activity in mice with passive EAE.
Table S1. Sequences of primers used for qPCR analysis.


File (5_ra38_sm.pdf)

References and Notes

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Published In

Science Signaling
Volume 5 | Issue 225
May 2012

Submission history

Received: 12 December 2011
Accepted: 4 May 2012


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We thank G. Kelsoe, T. Tedder, M. Krangel, D. Gunn, C. Gordy, and K. Kobayashi for critical discussions and reading of the manuscript. Funding: This study was funded by the National Multiple Sclerosis Society (RG4536-A-1) to M.L.S., the NIH (AI089756) to K.L.W., and a Methusalem grant from the Flemish government (BOF09/01M00709) to P.V. Author contributions: M.I. and M.L.S. designed the study, analyzed the data, and wrote the manuscript; M.I. performed most of the experiments; K.L.W. and P.V. contributed critical reagents and discussed the data; T.O. contributed microscope analyses; J.V.R. performed the experiments with S. typhimurium and p47phox-deficient cells; and E.A.M. analyzed the data. Competing interests: M.I. and M.L.S. have applied for a patent (US #13/347,233) based on this work. Data and materials availability: Use of the Nlrp3−/− and Asc−/− mice requires the signing of a materials transfer agreement (MTA).



Makoto Inoue
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Kristi L. Williams
Departments of Medicine and Cardiology, Duke University Medical Center, Durham, NC 27710, USA.
Timothy Oliver*
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Peter Vandenabeele
Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie (VIB), 9052 Ghent (Zwijnaarde), Belgium.
Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent (Zwijnaarde), Belgium.
Jayant V. Rajan
Institute for Systems Biology, Seattle, WA 98103, USA.
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Edward A. Miao
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Mari L. Shinohara [email protected]
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.


†To whom correspondence should be addressed. E-mail: [email protected]

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