CD27+CD11b+NK细胞PGE2受体亚型3(EP3)在肝纤维化中的作用及机制研究

自然杀伤细胞(NK)是肝脏固有免疫反应的重要组成部分，可通过杀伤星状细胞（HSC）抑制肝纤维化。前列腺素（PG）是免疫调控的重要介质，但PG是否通过调控NK细胞影响肝纤维进程目前尚不清楚。我们前期发现敲除PGE2受体EP3明显加重小鼠肝纤维化，降低NK细胞CD27+CD11b+亚群杀伤HSC的能力，并使胞内Ca2+水平下降，转录因子NFAT2核转位减少，IFN-γ表达降低。推测EP3受体通过Ca2+/NFAT2信号通路活化NK细胞，从而缓解肝纤维化损伤。本课题拟使用EP3条件敲除和过表达小鼠，进一步明确EP3对CD27+CD11b+亚群功能的影响以及在肝纤维化中的作用；揭示EP3介导下的Ca2+/Calcineurin/NFAT2信号通路在NK杀伤HSC中的作用；解析与EP3偶联的G蛋白系统在此信号转导中的作用；探讨EP3激动剂对肝纤维化的治疗作用，为肝纤维化的治疗提供潜在的靶点。

Natural killer cells (NK) are an important component of the liver's innate immunity and can inhibit liver fibrosis by killing hepatic stellate cells(HSC). Prostaglandins (PG) are important mediators of immune regulation, but it is unclear whether PG affects liver fiber progression by regulating NK cell activity. We have previously found that deletion of PGE2 receptor EP3 significantly reduced the function of CD27+CD11b+ NK subsets to kill HSC，aggravated liver fibrosis in mice，decreased the intracellular Ca2+ level，inhibited NFAT2 nuclear translocation and IFN-γ expression.We speculated that the EP3 receptor can activate NK cells through the Ca2+/NFAT2 signaling pathway, thereby alleviating liver fibrosis damage.To prove the hypothesis, the function of CD27+CD11b+ NK subsets and its role in liver fibrosis will be evaluated in EP3 receptor NK cells conditional knockout and overexpressed mice,the role of Ca2+/Calcineurin /NFAT2 signaling pathway mediated by EP3 will be tested, and the fuction of EP3 receptor coupled G proteins will be analyzed in CD27+CD11b+ NK subsets. Finally,the therapeutic effect of EP3 agonists on hepatic fibrosis will be explored. Our study will provide a potential target for the treatment of liver fibrosis.