The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases  

作　　者：Qiang Qin Huan Liu Jia’nan Shou Yu Jiang Hong Yu Xiaojian Wang 

机构地区：[1]Department of General Surgery,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,Hangzhou 310016,PR China [2]lnstitute of Immunology,School of Medicine,Zhejiang University,Hangzhou 310058,PR China [3]Department of Clinical Laboratory Medicine,Second Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou 310009,PR China

出　　处：《Cellular & Molecular Immunology》2021年第4期992-1004,共13页中国免疫学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(81972733);the Natural Science Foundation of Zhejiang Province(LY19H160048).

摘　　要：Aberrant inflammasome activation contributes to the pathogenesis of various human diseases,including atherosclerosis,gout,and metabolic disorders.Elucidation of the underlying mechanism involved in the negative regulation of the inflammasome is important for developing new therapeutic targets for these diseases.Here,we showed that Raf kinase inhibitor protein(RKIP)negatively regulates the activation of the NLRP1,NLRP3,and NLRC4 inflammasomes.RKIP deficiency enhanced caspase-1 activation and IL-1P secretion via NLRP1,NLRP3,and NLRC4 Inflammasome activation In primary macrophages.The overexpression of RKIP in THP-1 cells inhibited NLRP1,NLRP3,and NLRC4 inflammasome activation.RKIP-deficient mice showed increased sensitivity to Aluminduced peritonitis and Salmonella typhimurium-induced inflammation,indicating that RKIP inhibits NLRP3 and NLRC4 inflammasome activation in vivo.Mechanistically,RKIP directly binds to apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC)and competes with NLRP1,NLRP3,or NLRC4 to interact with ASC thus interrupting inflammasome assembly and activation.The depletion of RKIP aggravated inflammasome-related diseases such as monosodium urate(MSU)-induced gouty arthritis and high-fat diet(HFD)-induced metabolic disorders.Furthermore,the expression of RKIP was substantially downregulated in patients with gouty arthritis or type 2 diabetes(T2D)compared to healthy controls.Collectively,our findings suggest that RKIP negatively regulates NLRP1,NLRP3,and NLRC4 inflammasome activation and is a potential therapeutic target for the treatment of inflammasome-related diseases.

关 键 词：Raf kinase inhibitor protein(RKIP) INFLAMMASOME Gouty arthritis HFD-induced metabolic disorders 

分 类 号：R392[医药卫生—免疫学]