An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage.

Inflammation induced by innate immunity influences the development of T cell-mediated autoimmunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). We found that strong activation of innate immunity induced Nod-like receptor protein 3 (NLRP3) inflammasome-independent and interferon-β (IFNβ)-resistant EAE (termed type B EAE), whereas EAE induced by weak activation of innate immunity requires the NLRP3 inflammasome and is sensitive to IFNβ treatment. Instead, an alternative inflammatory mechanism, including membrane-bound lymphotoxin-β receptor (LTβR) and CXC chemokine receptor 2 (CXCR2), is involved in type B EAE development, and type B EAE is ameliorated by antagonizing these receptors. Relative expression of Ltbr and Cxcr2 genes was indeed enhanced in patients with IFNβ-resistant multiple sclerosis. Remission was minimal in type B EAE due to neuronal damages induced by semaphorin 6B upregulation on CD4+ T cells. Our data reveal a new inflammatory mechanism by which an IFNβ-resistant EAE subtype develops.