Tabersonine,a natural NLRP3 inhibitor,suppresses inflammasome activation in macrophages and attenuate NLRP3-driven diseases in mice  

作　　者：Hao-wen Xu Wei-feng Li Shan-shan Hong Jing-jing Shao Jia-hao Chen Nipon Chattipakorn Di Wu Wu Luo Guang Liang 

机构地区：[1]Department of Cardiology and Medical Research Center,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou 325035,China [2]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China [3]School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou 311399,China [4]Cardiac Electrophysiology Research and Training Center,Faculty of Medicine,Chiang Mai University,Chiang Mai 50200,Thailand

出　　处：《Acta Pharmacologica Sinica》2023年第6期1252-1261,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(21961142009 to GL,82000793 to WL);Thailand Research Fund Grant(DBG6280006 to NC);Natural Science Foundation of Zhejiang Province(LY22H070004 to WL);Wenzhou Scientific Project in China(Y20210213 to WL);Zhejiang Provincial Key Scientific Project(2021C03041 toGL).

摘　　要：Aberrant activation of NLRP3 inflammasome causes the progression of various inflammation-related diseases,but the small-molecule inhibitors of NLRP3 are not currently available for clinical use.Tabersonine(Tab)is a natural product derived from a traditional Chinese herb Catharanthus roseus that is usually used as an anti-tumor agent.In this study we investigated the anti-inflammatory effects and molecular targets of Tab.We first screened 151 in-house natural compounds for their inhibitory activity against IL-1βproduction in BMDMs.We found that Tab potently inhibited NLRP3-mediated IL-1βproduction with an IC50 value of 0.71μM.Furthermore,we demonstrated that Tab suppressed the assembly of NLRP3 inflammasome,especially the interaction between NLRP3 and ASC.Interestingly,we found that Tab directly bound to NLRP3 NACHT domain,thereby reducing the self-oligomerization of NLRP3.In addition,we showed that administration of Tab significantly ameliorated NLRP3-driven diseases,such as peritonitis,acute lung injury,and sepsis in mouse models.The preventive effects of Tab were not observed in the models of NLRP3 knockout mouse.In conclusion,we have identified Tab as a natural NLRP3 inhibitor and a lead compound for the design and discovery of novel NLRP3 inhibitors.

关 键 词：tabersonine NLRP3 inflammasome NACHT domain acute lung injury PERITONITIS SEPSIS 

分 类 号：R742.5[医药卫生—神经病学与精神病学]