Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome
Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome
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胆汁酸通过抑制 NLRP3 炎症小体控制炎症和代谢紊乱
DOI：
10.1016/j.immuni.2016.09.008
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发表时间：
2016-10-18
期刊：
影响因子：
32.4
通讯作者：
Wang, Di
中科院分区：
文献类型：
--
作者：
Guo, Chuansheng;Xie, Shujun;Wang, Di
代谢系统和免疫细胞之间的相互作用在各种炎症性疾病中起着关键作用，但其潜在机制仍然难以捉摸。胆汁酸介导的信号传导的激活与代谢综合征的改善和炎症的增强控制有关。在这里，我们证明了胆汁酸通过TGR 5-cAMP-PKA轴抑制NLRP 3炎性小体活化。TGR 5胆汁酸受体诱导的PKA激酶激活导致NLRP 3的泛素化，这与PKA诱导的NLRP 3在单个残基Ser 291上的磷酸化有关。此外，这种PKA诱导的NLRP 3磷酸化对NLRP 3炎性体活化起关键制动作用。此外，体内结果表明，胆汁酸和TGR 5激活阻断NLRP 3炎性体依赖性炎症，包括脂多糖诱导的全身性炎症，明矾诱导的腹膜炎症和2型糖尿病相关炎症。总之，我们的研究揭示了PKA诱导的NLRP 3磷酸化和泛素化，并表明TGR 5作为治疗NLRP 3炎性小体相关疾病的潜在靶点。
Reciprocal interactions between the metabolic system and immune cells play pivotal roles in diverse inflammatory diseases, but the underlying mechanisms remain elusive. The activation of bile acidmediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Here, we demonstrated that bile acids inhibited NLRP3 inflammasome activation via the TGR5-cAMP-PKA axis. TGR5 bile acid receptorinduced PKA kinase activation led to the ubiquitination of NLRP3, which was associated with the PKA-induced phosphorylation of NLRP3 on a single residue, Ser 291. Furthermore, this PKA-induced phosphorylation of NLRP3 served as a critical brake on NLRP3 inflammasome activation. In addition, in vivo results indicated that bile acids and TGR5 activation blocked NLRP3 inflammasome-dependent inflammation, including lipopolysaccharideinduced systemic inflammation, alum-induced peritoneal inflammation, and type-2 diabetes-related inflammation. Altogether, our study unveils the PKA-induced phosphorylation and ubiquitination of NLRP3 and suggests TGR5 as a potential target for the treatment of NLRP3 inflammasome-related diseases.