RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor

摘要

The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory,metabolic and neurodegenerative diseases,but medications targeting the NLRP3 inflammasome are not available for clinical use.RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials,but its effects on inflammatory diseases are not known.Here,we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory diseases.RRx-001 inhibits the activation of the canonical,noncanonical,and alternative NLRP3 inflammasomes but not the AIM2,NLRC4 or Pyrin inflammasomes.Mechanistically,RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction,which is critical for the assembly and activation of the NLRP3 inflammasome.More importantly,RRx-001 treatment attenuates the symptoms of lipopolysaccharide(LPS)-induced systemic inflammation,dextran sulfate sodium(DSS)-induced colitis and experimental autoimmune encephalomyelitis(EAE)in mice.Thus,our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.