A Small-molecule Inhibitor B57 Play A Role In The Process Of NLRP3 Inflammasome Activation

Inflammsome is an intracellular signaling complex in innate immune system.The activation of inflammsome leads to the maturation and secretion of interleukin-1?(IL-1?)and interleukin(IL-18),and then trigger pyroptosis by the activation of Gasdermin D.A series of studies shown that the activated NLRP3 inflammasome requires to recruit adaptor ASC and resulting in the formation of ASC speck,then promote inflammasome ralated Caspase-1 activation.The recruitment of ASC to NLRP3 may play a important role in the process of NLRP3 inflammasome assembly.Here,to identify a regulatory system for activation of the NLRP3 inflammasome,we found a compound called B57,a potent selective,small-molecule inhibitor of NLRP3 by screening of a macrophage cell line Raw-asc with a chemical compound library.The activation and secretion of Caspase-1 and IL-1? were blocked by using B57.B57 specifically inhibited activation of NLRP3 but not NLRC4 or AIM2 inflammasome.To further explored the mechanism of B57 could inhibit the NLRP3 inflammsome activation,an adaptor of NLRP3.We found that the oligomerization of ASC and the interaction of ASC with NLRP3 was abrogated.But it didn't affect the NLRP3 oligomerization and the interaction of NLRP3 itself.Finally,we explored the small-molecular compound inhibitor function in the mice disease model.The monosodium urate crystals(MSU)induced NLRP3 activation resulting in peritonitis symptoms in mice.B57 could significantly decrease the infiltration of Ly6G+-neutrophils,as well as IL-1? production in the peritoneal cavity.In this experiment,based on a small-molecule B57 in NLRP3 activation process researching and function analysis,we provided a potential targets for new drug development for the treatment of NLRP3 inflammasome related diseases.