Acetate attenuates inflammasome activation through GPR43-mediated Ca2+-dependent NLRP3 ubiquitination
Acetate attenuates inflammasome activation through GPR43-mediated Ca2+-dependent NLRP3 ubiquitination
复制标题
乙酸通过 GPR43 介导的 Ca2 依赖性 NLRP3 泛素化减弱炎症小体激活
DOI：
10.1038/s12276-019-0276-5
复制
发表时间：
2019-07-23
影响因子：
12.8
通讯作者：
Deng, Xiaoming
中科院分区：
文献类型：
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作者：
Xu, Mengda;Jiang, Zhengyu;Deng, Xiaoming
醋酸酯已被证明在炎症性和代谢性疾病中升高并调节炎症。炎性小体是免疫稳态的关键组成部分，其失调可导致各种炎症性疾病。然而，关于醋酸酯对炎症小体激活的影响及其潜在机制知之甚少。在这里，我们证明醋酸通过GPR43以Ca2+依赖的方式减弱炎性体的激活。通过与GPR43结合，醋酸酯激活G（q/11）亚基和随后的磷脂酶C-IP3信号，以减少Ca2+的动员。此外，乙酸激活可溶性腺苷酸环化酶（sAC），通过PKA促进NLRP3炎性体泛素化，最终通过自噬诱导NLRP3降解。在体内，醋酸酯可以保护小鼠免受NLRP3炎性小体依赖性腹膜炎和lps诱导的内毒素血症。总之，我们的研究表明，醋酸盐通过GPR43和Ca2+依赖机制调节NLRP3炎症小体，这揭示了代谢物介导的NLRP3炎症小体衰减的机制，并突出了醋酸盐作为NLRP3炎症小体相关疾病的可能治疗策略。
Acetate has been indicated to be elevated and to regulate inflammation in inflammatory and metabolic diseases. The inflammasome serves as a key component of immune homeostasis, and its dysregulation can lead to various inflammatory disorders. However, little is known about the effects of acetate on inflammasome activation and the underlying mechanism. Here, we demonstrate that acetate attenuates inflammasome activation via GPR43 in a Ca2+-dependent manner. Through binding to GPR43, acetate activates the G(q/11) subunit and subsequent phospholipase C-IP3 signaling to decrease Ca2+ mobilization. In addition, acetate activates soluble adenylyl cyclase (sAC), promotes NLRP3 inflammasome ubiquitination by PKA, and ultimately induces NLRP3 degradation through autophagy. In vivo, acetate protects mice from NLRP3 inflammasome-dependent peritonitis and LPS-induced endotoxemia. Collectively, our research demonstrates that acetate regulates the NLRP3 inflammasome via GPR43 and Ca2+-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasome attenuation and highlights acetate as a possible therapeutic strategy for NLRP3 inflammasome-related diseases.