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

Characterization of an animal model may explain why not all patients with multiple sclerosis respond to interferon-β. 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.