低自噬子宫内膜间质细胞通过Hck诱导CD56+CD16-NK细胞分化参与内异症发病的分子机制

There is strong evidence to support the role of abnormal immune response of peritoneal environment in endometriosis. Instead of leading to the clearance of regurgitated endometrial cells in pelvic cavity, dysregulated immune cells from endometriotic milieu are thought to favor the implantation and growth of ectopic endometrial tissue. Recently, we have found that the ratio of CD56+CD16- NK cells in peritoneal fluid is increased in endometriosis (stage III-IV), and the autophagy level is significantly lower in endometriosis-derived endometrial stromal cells (ESCs), as well as the expression of CD16-related hematopoietic cellular kinase (Hck). And ectopic ESCs could induce the CD56+CD16- NK cells differentiation in vitro. However, the mechanism behind the CD56+CD16- NK cell differentiation and its role in the progression of endometriosis is still unknown. Therefore, the aim of this study is to investigate how ESC autophagy in the endometriotic milieu regulates the CD56+CD16- NK cells differentiation through Hck and its downstream cytokines, and how these educated NK cells effect on the initiation and progression of endometriosis in vivo and in vitro. These findings have implications for future therapeutic strategies specifically targeting the abnormal autophagy in endometriosis.

研究显示子宫内膜异位症患者盆腹腔局部免疫微环境异常，免疫细胞不仅不能清除异位子宫内膜，反而促进其种植生长。我们近期发现，内异症患者腹腔液中CD56+CD16-NK细胞比例增加，异位病灶子宫内膜间质细胞（ESC）自噬水平降低，同时与CD16作用相关的造血细胞激酶（Hck）在低自噬ESC中也显著下降。将低自噬ESC与外周NK细胞体外共培养可以促进CD56+CD16-NK细胞分化。然而低自噬ESC是否通过Hck诱导CD56+CD16-NK细胞分化，耐受型NK细胞在内异症发病中发挥什么作用，这些均不清楚。本课题构建体外共培养体系和内异症小鼠模型，拟解析低自噬水平ESC通过Hck介导CD56+CD16-NK细胞分化的分子机制，进一步探讨CD56+CD16-NK细胞调控子宫内膜生长和侵袭参与EMs发病的分子机制。本课题将为内异症发病机制的研究提供新的研究方向，为寻找内异症的防治新策略提供科学依据。

增进和维护妇女生殖健康是当今全球卫生战略面临的严峻课题之一。子宫内膜异位症虽为良性病变，但却具有增生、种植浸润、转移和复发等类似于恶性肿瘤的行为，患者呈现渐进性加重的盆腔粘连、疼痛甚至不孕，对育龄期妇女的身心健康造成极大的危害，但是其具体机制不甚明确。我们研究发现低细胞毒性FCGR3- NK细胞在EMs患者腹腔液中比例升高，同时低自噬水平ESC共培养后NK细胞呈现低细胞毒性的FCGR3- NK细胞表型。进一步以体外构建细胞共培养体系模拟EMs盆腹腔微环境和体内动物实验为研究手段，发现低自噬ESC通过HCK-CXCL8/IL23A途径激活STAT3下游信号通路，进而诱导NK细胞分化。而经低自噬水平诱导的NK细胞中MIR1185-1-3p水平上调，通过调控PTGS2表达参与FCGR3- NK细胞的诱导分化。PTGS2+ FCGR3-NK细胞低表达细胞因子PRF1、GZMB和IFNG，并促进内异症异位病灶的生长，参与内异症的发生发展。. 综上，本研究重点通过阐述EMs来源低自噬ESCs对FCGR3+ NK细胞与FCGR3- NK细胞之间的平衡调节，证实低自噬ESCs和FCGR3- NK细胞参与子宫内膜异位症发生和发展，为内异症诊治寻找新靶点提供理论依据。科研成果的临床转化，为临床内异症的诊治提供潜在靶点，有利于改善内异症患者症状，减轻内异症患者心理及经济负担，带来社会和经济效益。

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