title: Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.
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.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Williams
authors.forename: Timothy
authors.initials: T
authors.lastname: Oliver
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: Jayant V
authors.initials: JV
authors.lastname: Rajan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Miao
authors.forename: Mari L
authors.initials: ML
authors.lastname: Shinohara
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000172:deficiency; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D058847:Inflammasomes / Q000502:physiology*; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav / Q000037:antagonists & inhibitors / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000502:physiology*; D011994:Recombinant Proteins / Q000627:therapeutic use; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D020830:rac1 GTP-Binding Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C508032:Ifnar1 protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009479:Neuropeptides; C492716:Nlrp3 protein, mouse; D051567:Proto-Oncogene Proteins c-vav; C498534:Pycard protein, mouse; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C496619:Vav1 protein, mouse; D000068576:Interferon beta-1b; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D020170:Caspase 1; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein