The Effect And Mechanism Of NS1619 In Inhibiting NLRP3 Inflammasome Activation

The direct recognition of invading pathogens by innate immune cells is a key driver to initiate the inflammatory response.Pattern recognition receptors of the innate immunity detect pathogenic microbial conservative motifs and endogenous danger signals,resulting in the activation of the downstream signals to induce the immune response.NLRP3 is one of the important pattern recognition receptors.After sensing stimulus such as microbial infection and tissue damage,it binds to adaptor ASC,which in turn interacts with effector caspase-1 to form a complex known as the NLRP3 inflammasome.The assembly leads to the activation of caspase-1,which then cleaves the inactive cytosolic precursors,such as pro-IL-1? and pro-IL-18,into their mature forms IL-1? and IL-18 and causes pyroptosis,which triggers the inflammatory response.Although NLRP3 inflammasome plays a key role in the innate immune activation and inflammatory response,its excessive activation can lead to tissue damage,and cause inflammatory diseases.Therefore,the activation of NLRP3 inflammasome needs to be strictly regulated to achieve the precise response of the immune system.However,there is currently no clinical drug targeting NLRP3 inflammasome.NS1619 is an activator of large-conductance calcium-dependent potassium channels,which can regulate physiological processes such as intracellular calcium levels,smooth muscle relaxation,and cell excitability.Related studies have shown that NS 1619 has a good intervention effect on asthma,diabetes and other disease models,but its role and mechanism in the activation of immune cells and the occurrence of inflammatory response are still unclear.This study found that NS 1619 could inhibit the oligomerization of NLRP3,thereby inhibiting the assembly of NLRP3 inflammasome and preventing the secretion of pro-inflammatory cytokines such as IL-1?.Furthermore,we found that NS 1619 could relieve MSU-induced peritonitis in mice.In conclusion,our study indicates that NS 1619 is a strong NLRP3 inflammasome inhibitor,suggesting that it may become a potential lead compound for the development of NLRP3 inflammasome-related intervention drugs.