Suppression of autophagy and HCK signaling promotes PTGS2high FCGR3− NK cell differentiation triggered by ectopic endometrial stromal cells

作者：Jie Mei, Wen‐Jie Zhou, Xiao‐Yong Zhu, Han Lü, Ke Wu, Hui‐Li Yang, Qiang Fu, Chunyan Wei, Kai‐Kai Chang, Liping Jin, Jian Wang, Yongming Wang, Da‐Jin Li, Ming‐Qing Li · 发表于：Autophagy · 年份：2018 · DOI：10.1080/15548627.2018.1476809 · 被引用次数：60 · 研究领域：Endometriosis Research and Treatment、Reproductive System and Pregnancy、Endometrial and Cervical Cancer Treatments

Impaired NK cell cytotoxic activity contributes to the local dysfunctional immune environment in endometriosis (EMS), which is an estrogen-dependent gynecological disease that affects the function of ectopic endometrial tissue clearance. The reason for the impaired cytotoxic activity of NK cells in an ectopic lesion microenvironment (ELM) is largely unknown. In this study, we show that the macroautophagy/autophagy level of endometrial stromal cells (ESCs) from EMS decreased under negative regulation of estrogen. The ratio of peritoneal FCGR3− NK to FCGR3+ NK cells increases as EMS progresses. Moreover, the autophagy suppression results in the downregulation of HCK (hematopoietic cellular kinase) by inactivating STAT3 (signal transducer and activator of transcription 3), as well as the increased secretion of the downstream molecules CXCL8/IL8 and IL23A by ESCs, and this increase induced the upregulation of FCGR3− NK cells and decline of cytotoxic activity in ELM. This process is mediated through the depression of microRNA MIR1185-1-3p, which is associated with the activation of the target gene PTGS2 in NK cells. FCGR3− NK with a phenotype of PTGS2/COX2high IFNGlow PRF1low GZMBlow induced by hck knockout (hck−/-) or 3-methyladenine (3-MA, an autophagy inhibitor)-stimulated ESCs accelerates ESC’s growth both in vitro and in vivo. These results suggest that the estrogen-autophagy-STAT3-HCK axis participates in the differentiation of PTGS2high IFNGlow PRF1low GZMBlow FCGR3− NK cel...