The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases
The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases
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DOI：
10.1038/s41423-020-00525-3
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发表时间：
2020-09-08
影响因子：
24.1
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
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作者：
Qin, Qiang;Liu, Huan;Wang, Xiaojian
异常的炎性体活化有助于多种人类疾病的发病机制，包括动脉粥样硬化、痛风和代谢紊乱。阐明炎性小体负调控的潜在机制对于开发这些疾病的新治疗靶点非常重要。在这里，我们发现Raf激酶抑制蛋白（RKIP）负调控NLRP 1，NLRP 3和NLRC 4炎性小体的激活。RKIP缺陷通过NLRP 1、NLRP 3和NLRC 4炎性体激活增强原代巨噬细胞中的半胱天冬酶-1激活和IL-1 β分泌。RKIP在THP-1细胞中的过表达抑制了NLRP 1、NLRP 3和NLRC 4炎性小体的活化。RKIP缺陷小鼠对明矾诱导的腹膜炎和沙门氏菌诱导的炎症表现出增加的敏感性，表明RKIP抑制体内NLRP 3和NLRC 4炎性体激活。在机制上，RKIP直接结合到含有半胱天冬酶募集结构域（ASC）的骨化相关斑点样蛋白，并与NLRP 1、NLRP 3或NLRC 4竞争与ASC相互作用，从而中断炎性小体组装和活化。RKIP的缺失加重了炎性小体相关疾病，如尿酸盐（MSU）诱导的痛风性关节炎和高脂饮食（HFD）诱导的代谢紊乱。此外，与健康对照组相比，痛风性关节炎或2型糖尿病（T2 D）患者的RKIP表达显著下调。总的来说，我们的研究结果表明，RKIP负调控NLRP 1，NLRP 3和NLRC 4炎性小体激活，是治疗炎性小体相关疾病的潜在治疗靶点。
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-1 beta 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 Alum-induced peritonitis andSalmonella 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.