Immunity:我国学者揭示代谢与免疫新机制
浙江大学医学院王迪教授通过构建动物疾病模型,结合免疫学、细胞生物学和生物化学等研究手段,发现胆酸可以通过抑制NLRP3炎症小体从而改善炎症性疾病,如脓毒症、腹腔炎以及二型糖尿病等的发生,揭示了脂代谢通路蛋白参与炎症性疾病发生发展的新机制。


在国家自然科学基金优秀青年科学基金(项目编号:31522020)和面上项目(项目编号:31270017)等资助下,浙江大学医学院王迪教授通过构建动物疾病模型,结合免疫学、细胞生物学和生物化学等研究手段,发现胆酸可以通过抑制NLRP3炎症小体从而改善炎症性疾病,如脓毒症、腹腔炎以及二型糖尿病等的发生,揭示了脂代谢通路蛋白参与炎症性疾病发生发展的新机制。

研究成果以“Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome(胆酸通过抑制NLRP3炎症小体调控炎症和机体代谢失调)”为题于2016年10月18日在Immunity发表。论文链接: http://dx.doi.org/10.1016/j.immuni.2016.09.008。

当前人类多数顽疾均与免疫系统紊乱相关,而免疫系统受代谢系统的密切调控,免疫系统通过改变代谢显著影响代谢性疾病的进程,这使得代谢免疫学成为当今重要的新兴学科。 胆酸作为胆汁的关键组分之一, 以往被认为是重要的代谢调节物,在脂类代谢中发挥重要作用。近年来,越来越多的研究显示:胆酸还发挥着重要的激素调节作用,可以通过激活多种受体发挥复杂的生理和病理功能。

王迪教授课题组的研究发现,胆酸通过TGR5受体激活PKA激酶进而直接磷酸化NLRP3 291位点的丝氨酸,导致NLRP3的泛素化;功能实验证实,这两种PKA引起的NLRP3蛋白翻译后修饰,在抑制NLRP3炎症小体活化过程中发挥着重要的作用。同时该分子机制也有可能参与到某些NLRP3炎症小体过度活化导致的炎症性疾病的发病机制当中。


图 胆酸分子(Bile acids)通过TGR5-cAMP-PKA信号转导通路抑制NLRP3炎症小体活化

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  • Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome

    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.

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