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

Abstract

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

New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

“…For this reason, the remainder of this review will focus on IL-1β, although whether IL-1α plays any role in MS remains an open question. Consistent with a critical requirement for IL-1β for EAE susceptibility, mice deficient in the inflammasome components NLRP3 (37–41), ASC (36, 39, 42), caspase 1 (42, 43), and caspase 11 (44) were also at least partially resistant to EAE, as were mice treated with inhibitors of NLRP3 (45, 46) or caspase 1 (47). It is worth noting that in some reports (40–42), mice immunized with larger amounts of heat-killed Mycobacterium tuberculosis ( Mtb ) (usually greater than 300 micrograms per mouse) as part of the MOG 35-55 /CFA emulsion developed an NLPR3- and ASC-independent form of aggressive EAE.…”

Direct Antimicrobial Activity of IFN-β

“…1B). Such doses of IFN-β are not unusual in the literature and are thought to be biologically relevant (22–25). Having observed killing of S. aureus after incubation with IFN-β, we examined whether these antibacterial properties were effective against other species of bacteria.…”

Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE)

“…Mild EAE by the lack of NLRP3, ASC and caspase-1 points collectively to the involvement of the NLRP3 inflammasome in the disease. Additionally, IFNb, a first line therapeutic for MS, functioned to suppress NLRP3 inflammasome activation and its effects in EAE, protecting mice from the disease (36,38). Additionally, IFNb, a first line therapeutic for MS, functioned to suppress NLRP3 inflammasome activation and its effects in EAE, protecting mice from the disease (36,38).…”

“…This NLRP3-independent IFNb-resistant EAE subtype can be sufficiently induced with high doses of adjuvant (heat-killed Mycobacteria in EAE) (36). Indeed, acute virus infection also "converted" NLRP3 inflammasome-dependent EAE to NLRP3 inflammasome-independent IFNb-resistant disease (36). Indeed, acute virus infection also "converted" NLRP3 inflammasome-dependent EAE to NLRP3 inflammasome-independent IFNb-resistant disease (36).…”