雌激素通过抑制ESC自噬调节异位灶微环境NK细胞分化的分子机制

It has been reported the abnormal local immune microenvironment in abdominal from women with endometriosis cannot effectively remove endometrial stromal cells (ESC) of the ectopic foci. In contrast, it can promote the growth and implantation of ESC. Recent studies suggest that ectopic endometrial lesions have lower level of autophagy. We found that estrogen inhibited ESC autophagy by promoting the expression of CXCL12/CXCR4 in ESC. The ratio of CD16-NK to CD16+NK in peritoneal fluid was gradually increased with the progress of disease, especially in stage III-IV. Our researches showed that low levels of ESC autophagy mediated by estrogen could induce CD16-NK cells differentiation in vitro by down-regulating Hck (Hematopoietic Cellular Kinase) expression in ESC, but the molecular mechanisms and its role in the development of endometriosis are unclear. Therefore, takeing advantege of in vitro trials for imitating the abdominal microenvironment in endometriosis and in vivo animal experiments, our study intends to investigate the downstream signal pathways which are involved in low level of ESC autophagy mediated by estrogen-CXCL12 signaling on CD16-NK differentiation, and to further explore whether these CD16-NK cells promote the progress of endometriosis by regulating the biological behaviors of ESC. This project will provide a new direction for researching the pathogenesis of endometriosis, and the scientific basis for finding new strategies in the prevention and treatment of endometriosis.

研究显示子宫内膜异位症（简称内异症）患者盆腹腔局部免疫微环境异常，不仅不能清除异位灶内膜间质细胞（ESC）且促进其异位生长种植。近来研究提示异位灶内膜自噬水平降低。我们近期发现雌激素通过促进ESC表达CXCL12/CXCR4抑制ESC自噬。随着疾病进展，III-IV期患者腹腔液中CD16-NK/CD16+NK的比值升高。体外实验显示雌激素诱导的低自噬ESC，通过下调ESC中Hck表达可诱导CD16-NK分化，但确切的分子机制及其在内异症发展中的作用尚不清楚。故本课题以体外模拟内异症盆腹腔微环境和体内动物实验为研究手段，拟研究雌激素-CXCL12信号诱导的低自噬ESC通过何种下游信号诱导异位灶微环境 CD16-NK分化，进一步解析这群CD16-NK细胞是否通过调节ESC生物学行为促进内异症进展的病理机制。本课题将为内异症发病机理研究提供新的研究方向，为寻找防治内异症的新策略提供科学依据。

研究显示简称子宫内膜异位症（endometriosis, EMS）患者盆腹腔局部免疫微环境异常，不仅不能清除异位灶内膜间质细胞（ESC）且促进其异位生长种植。NK细胞作为构成腹膜清除系统的重要细胞，其细胞毒作用的减弱在EMS的发生和发展中的作用早有报道，然而其分子机制尚不明确。我们研究发现随着EMS疾病进展，患者腹腔液中FCGR3/CD16-NK细胞的比例逐渐升高。一旦雌激素浓度异常升高，引起ESC自噬水平降低。低自噬水平的异位灶ESC可以通过STAT3导致HCK表达下降，进一步通过分泌更高水平IL-8和IL-23A，上调NK细胞MIR1185-1-3P的转录，促进PTGS2/COX-2highCD16-NK细胞分化。相对于COX-2-CD16+NK细胞，COX-2highCD16-NK细胞高表达IL-10和TGF-β，低表达细胞毒活性分子。这群低细胞毒活性NK细胞不仅对异位灶免疫监视能力弱，且促进其异位种植生长。这些结果提示，雌激素-自噬-STAT3-Hck轴通过促进异位灶微环境中COX-2high IFNGlow PRF1low GZMBlow CD16−NK细胞分化，促进EMS进展。这一研究以“ESC自噬-免疫”调节通路为切入点，系统诠释解析了EMS异位灶逃脱NK细胞监视的生物学途径。在此基础上，我们发现人参原二醇PPD可以“雌激素受体-自噬和NK细胞”为共同靶点发挥抗EMS作用，具有临床治疗EMS的潜在价值。