胆酸对NLRP3炎症小体及相关炎症性疾病的调控功能与机制研究

Reciprocal interactions between the metabolic system and immune cells play pivotal roles in the pathogenesis of diverse inflammatory diseases, but the underlying mechanisms are still unclear. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Activation of the NLRP3 inflammasome triggers the caspase-1-dependent maturation and release of several pro-inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Excessive activation of the inflammasome is therefore involved in the pathogenesis of several inflammatory disorders, including type-2 diabetes (T2D), atherosclerosis, gout, and Alzheimer’s disease, suggesting that this activation needs to be tightly controlled. Although recent studies have extensively investigated the NLRP3 inflammasome, little is known about its regulatory networks, especially the endogenous mechanisms. Also, a better understanding of these regulatory mechanisms is required for the development of effective therapeutic treatment for NLRP3-related inflammatory diseases. Here we demonstrate that bile acids specifically inhibit NLRP3 inflammasome activation and related caspase-1 activation, IL-1β secretion and ASC speck formation. Moreover, the receptor involved in the inhibition of NLRP3 by bile acids might be the TGR5 receptor. In light of our study, targeting TGR5 may lead to new insights and treatments for NLRP3 inflammasome-related diseases.

机体的免疫系统与代谢系统之间的相互作用已经成为当前免疫学研究的重要前沿课题，二者的相互作用对于维持机体代谢平衡和免疫稳态起着重要的调节作用。NLRP3炎症小体活化引起的机体炎症被证实参与多种炎症性疾病包括代谢综合征的病理发生，寻找其内源性调控分子也成为治疗NLRP3相关疾病的重要突破口。本课题组在前期筛选抑制NLRP3炎症小体活化的体内代谢调节物时发现，胆酸具有广泛、强力且特异性的NLRP3炎症小体抑制作用，包括pro-caspase-1和pro-IL-1β的切割成熟、IL-1β和IL-18成熟形式的分泌以及ASC speck的形成等，而这种作用可能通过胆酸受体TGR5信号通路来实现。本课题拟在已有研究基础上结合体外实验和体内动物模型，深入研究胆酸调控NLRP3炎症小体活化和相关炎症性疾病的发生及其作用机制，为胆酸及其受体作为NLRP3相关炎症性疾病及代谢综合征的治疗靶点提供理论依据。

机体的免疫系统与代谢系统之间的相互作用已经成为当前免疫学研究的重要前沿课题，二者的相互作用对于维持机体代谢平衡和免疫稳态起着重要的调节作用。NLRP3炎症小体活化引起的机体炎症被证实参与多种炎症性疾病包括代谢综合征的病理发生，寻找其内源性调控分子也成为治疗NLRP3相关疾病的重要突破口。本课题组在前期筛选抑制NLRP3炎症小体活化的体内代谢调节物时发现，胆酸具有广泛、强力且特异性的NLRP3炎症小体抑制作用，包括pro-caspase-1和pro-IL-1β的切割成熟、IL-1β和IL-18成熟形式的分泌以及ASC speck的形成等。机制研究发现胆酸通过TGR5受体激活PKA激酶进而直接将NLRP3 291位点的丝氨酸磷酸化，并导致NLRP3的泛素化。随后的功能实验证实PKA引起的NLRP3蛋白291丝氨酸位点磷酸化和泛素化修饰在抑制NLRP3炎症小体活化过程中发挥重要的作用。进一步的小鼠体内实验证实胆酸可以通过抑制NLRP3炎症小体从而改善炎症性疾病的病理发生，包括脓毒症、腹腔炎以及二型糖尿病等。本论文的完成揭示了胆酸抗炎作用的新机制，为胆酸及其受体作为NLRP3相关炎症性疾病及代谢综合征的治疗靶点提供了理论依据。