| Inflammasome,critical component of the innate immune system,are intracellular multiprotein complexes that assemble in the cytosol to mediate inflammatory response against pathogen infections and tissue damage.Among identified inflammasome,NLRP3 inflammasome is the most intensely investigated.It is composed of receptor NLRP3,adaptor protein ASC,and Pro-caspasse-1.The activation of NLRP3 inflammation further mediates the self-cleavage and activation of pro-caspase-1.On the one hand,the activation of caspase-1 mediates the maturation and release of the inflammatory factors IL-1β and IL-18 to promote inflammation.On the other hand,it cleaves Gasdermin D to cause pyroptosis,an inflammatory form of cell death.The abnormal activation of NLRP3 inflammasome is closely related to the occurrence and development of a variety of human inflammatory diseases,so its activation needs to be strictly regulated.At present,finding specific inhibitors targeting NLRP3 inflammasome is an important strategy for the treatment of related diseases.Piperlongumine(PL)is a natural small molecule alkaloid isolated from Piper longum L.At present,it has been found that PL has certain therapeutic effect in some inflammatory disease models such as neuroinflammation and rheumatoid arthritis,but its specific anti-inflammatory mechanism is still unclear.Whether PL can regulate NLRP3 inflammasome signaling pathway to play an anti-inflammatory role,it has not been reported.In this study,it was found that PL could specifically inhibit the activation of NLRP3 inflammasome,but had no effect on the activation of NLRP4 or AIM2 inflammasome.Meanwhile,PL could also inhibit the pyroptosis mediated by NLRP3 inflammasome activation.The preliminary mechanism study found that PL blocked the assembly process of NLRP3 inflammasome by inhibiting the oligomerization of NLRP3 itself,which affected the subsequent interaction between NLRP3 and ASC and the oligomerization of ASC,to inhibit the activation of NLRP3 inflammasome.It was further proved that PL could inhibit the activation of NLRP3 inflammasome in vivo,and had a certain protective effect on related diseases.This study preliminarily revealed the anti-inflammatory mechanism of PL,and provided a scientific theoretical basis for its clinical application in the treatment of NLRP3 inflammasome-related diseases. |
