IL-22介导自噬信号通路抑制NLRP3炎性小体活化在药物性肝损伤中发挥肝保护效应的作用及机制研究

药物性肝损伤(DILI)发病人数日益增多，严重威胁人类健康，备受临床关注。研究表明NLRP3炎性小体通过活化促炎因子发挥级联放大炎症反应介导DILI发生，同时NLRP3炎性小体的活化受到细胞自噬的调控。最新研究发现IL-22可介导下游自噬信号通路活化，影响内质网应激，减轻氧应激损伤。我们前期研究发现IL-22不仅通过抑制氧应激诱导的炎症反应发挥肝保护效应，而且可以增强自噬，但确切调控机制尚未完全明了。据此，我们推测IL-22可能通过STAT3的磷酸化，调节与下游信号蛋白PKR相互作用，激活自噬通路，减轻炎性小体活化进而发挥肝保护。本课题拟通过野生型、IL-22基因敲除、肝脏特异性STAT3基因敲除小鼠诱导DILI模型并结合体外实验了解IL-22、自噬和NLRP3炎性体之间的关联性，进一步阐明IL-22介导自噬信号通路抑制NLRP3炎性小体活化在保护DILI中的作用及相关机制。

The incidence rate of drug-induced liver injury (DILI) is increased year by year. DILI has a great impact on public health and attracted much attention of clinicians. Some studies demonstrated NLRP3 inflammasome could promote and aggravate DILI by activating pro-inflammatory cytokines and inflammatory cytokine cascades. Meanwhile, inflammasome activation are restrained and regulated by autophagy. The update studies shown that IL-22 could activate autophagy, have an effect on endoplasmic reticulum stress and alleviate the injury from reactive oxygen species (ROS). Our previous study indicates that IL-22 plays a protective role in DILI not only by ROS suppression but inducing autophagy activation. However the precise mechanisms of which, remain unknown. Therefore, it is speculated that IL-22 could induce autophagy to restrain inflammasome activation, alleviate the liver injury by promote phosphorylation of STAT3, which could interaction with protein kinase R(PKR). Wild type, IL-22 gene knockout, liver–specific STAT3 gene knock-out mice will be used for drug-induced liver injury model, as well as ex vivo experiments would be adopted into the our study to explore the association among IL-22, autophagy and NLRP3 inflammasome. Furthermore, it would be clarified that the mechanisms of IL-22 induced the phosphorylation of STAT3 involved in autophagy regulating inflammasome in DILI.