IRAK-M Down-regulates the Activation of Microglial NLRP3 Inflammasome and GSDMD-Mediated Pyroptosis in Microglial through Inhibiting IRAK1/TRAF6 Combination During Experimental Autoimmune Encephalomyelitis

Abstract

Abstract The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is a protein complex which mediates pro-inflammatory response and pyroptosis. The activation of NLRP3 inflammasome triggers pyroptosis via cleavage of the pore-forming protein gasdermin D. Previous studies have demonstrated that NLRP3 inflammasome activation in microglial contributes to the pathogenesis of EAE, while Inhibition of microglial NLRP3 inflammasome and the subsequent pyroptosis attenuates the severity of EAE. In addition, Interleukin-1 receptor-associated kinase (IRAK)-M, mainly expressed in microglial in the central nervous system, negatively regulates the TLR4/IL-1R signaling pathway through inhibiting the phosphorylation of IRAK1 and dissociation of IRAK1 from MyD88/IRAK-4/IRAK-1 complex as well as the formation of IRAK-1 and TRAF6 complex. Our recent study suggests the protective effect of microglial IRAK-M in EAE mice. Therefore, we hypothesize that IRAK-M may alleviate IRAK1-induced NLRP3 inflammasome activation and pyroptosis through inhibiting dissociation of IRAK1 from MyD88/IRAK-4/IRAK-1 complex and the following association of IRAK1 and TRAF6. Here, we used IRAK-M knockout mice and their microglia to clarify the role of IRAK-M in EAE. We demonstrated that IRAK-M decreased the incidence rate and improved the clinical symptoms accompanied by mild demyelination in EAE mice, and which was parallel to the inhibition of microglial NLRP3 inflammasome activation, pyroptosis, and IRAK1/TRAF6 formation in EAE. Our findings fill the gap in knowledge of IRAK-M on activation of NLRP3 inflammasome and pyroptosis and provide a potential novel target for the therapeutic strategy of multiple sclerosis and NLRP3-related diseases.