Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Toxicology, Zhejiang University School of Public Health, Hangzhou 310058, China.
Immunity. 2016 Oct 18;45(4):802-816. doi: 10.1016/j.immuni.2016.09.008. Epub 2016 Sep 28.
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 acid-mediated 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 receptor-induced 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 lipopolysaccharide-induced 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.
代谢系统和免疫细胞之间的相互作用在多种炎症性疾病中起着关键作用，但潜在的机制仍难以捉摸。胆汁酸介导的信号激活与代谢综合征的改善和炎症的增强控制有关。在这里，我们证明胆汁酸通过 TGR5-cAMP-PKA 轴抑制 NLRP3 炎性体的激活。TGR5 胆汁酸受体诱导的 PKA 激酶激活导致 NLRP3 的泛素化，这与 PKA 诱导的 NLRP3 上单个残基 Ser291 的磷酸化有关。此外，这种 PKA 诱导的 NLRP3 磷酸化是 NLRP3 炎性体激活的关键制动。此外，体内结果表明，胆汁酸和 TGR5 激活阻断了 NLRP3 炎性体依赖性炎症，包括脂多糖诱导的全身炎症、明矾诱导的腹膜炎症和 2 型糖尿病相关炎症。总的来说，我们的研究揭示了 PKA 诱导的 NLRP3 磷酸化和泛素化，并表明 TGR5 是治疗 NLRP3 炎性体相关疾病的潜在靶点。
