4-Methylcatechol attenuates NLRP3 inflammasome activation to limit inflammation

NACHT-, LRR- and pyrin domain-containing protein 3 (NLRP3) is an intracellular sensor that detects exogenous pathogenic invasions and endogenous cellular damage, leading to the NLRP3 inflammasome activation, which plays vital roles in host defense and contributes to the pathogenesis of inflammatory diseases, such as acute peritonitis and gout. Therefore, targeting NLRP3 or other signaling molecules downstream has the potential therapeutic benefit. However, effective, low-toxic and clinically promising targeted inhibitors of NLRP3 inflammasome need to be further studied. Through compound library screening, we verified that 4-methylcatechol (4-MC), a polyphenol metabolite of quercetin, inhibited the activation of NLRP3 inflammasome at a low concentration without cytotoxicity, while did not affect the Nuclear Factor kappa B (NF-κB) activation. Mechanistically, 4-MC had no effect on NLRP3 expression, but its inhibitory effect on NLRP3 activation was restrained by increased intracelluar ROS. Moreover, 4-MC significantly ameliorated alum-induced peritonitis and LPS-induced sepsis in vivo. Thus, our research proposes a potential therapeutic drug for the intervention of NLRP3-related inflammatory diseases.