BACKGROUND The crosstalk between trophoblast cells and decidual NK cells plays an important role in the establishment and maintenance of normal pregnancy. Recent studies reported that autophagy can induce immune tolerance at the maternal fetal interface, while the mechanism remains unclear. METHODS Autophagy levels in the villi of normal and recurrent spontaneous abortion (RSA) patients were detected by transmission electron microscopy. After co-cultured with trophoblast cells pretreated with 3-MA or rapamycin, NK cells were collected and the expression of killer receptors was detected by flow cytometry (FCM). The invasiveness of trophoblasts was tested by Cell invasion assay. RESULTS Compared with elective pregnancy termination patients, the level of autophagy in the villi of RSA patients was significantly decreased. Inducing the autophagy level in trophoblast cells with rapamycin could significantly inhibit the cytotoxicity of NK cells in the co-culture system, and supplement of IGF-2 could rectify this effect. Meanwhile, autophagy suppression of trophoblasts reduced the level of Paternally Expressed Gene 10 (PEG10), leading to the impairment of trophoblast cell invasion. In addition, NK cells educated by autophagy-inhibited trophoblasts further decreased the proliferation and invasiveness of trophoblasts. In pregnant mice model, injection with 3-MA promoted the cytotoxicity of uterine NK cells, and increased the embryo absorption rate. CONCLUSION Autophagy suppression of trophoblasts increase the cytotoxicity of NK cells and damage the trophoblasts invasion possibly by targeting IGF-2 and PEG10, respectively, which ultimately leads to miscarriage. Video Abstarct.

中文翻译：

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滋养层细胞的自噬抑制通过激活蜕膜 NK 细胞毒性和抑制滋养层侵袭而导致流产。

背景技术滋养层细胞与蜕膜NK细胞之间的串扰在正常妊娠的建立和维持中发挥着重要作用。最近的研究报道，自噬可以诱导母胎界面的免疫耐受，但其机制尚不清楚。方法采用透射电镜检测正常和复发性流产（RSA）患者绒毛中自噬水平。与经3-MA或雷帕霉素预处理的滋养层细胞共培养后，收集NK细胞，并通过流式细胞术（FCM）检测杀伤受体的表达。通过细胞侵袭实验检测滋养层细胞的侵袭能力。结果与选择性终止妊娠患者相比，RSA患者绒毛自噬水平显着降低。用雷帕霉素诱导滋养层细胞的自噬水平可以显着抑制共培养系统中NK细胞的细胞毒性，而补充IGF-2可以纠正这种作用。同时，滋养层细胞自噬抑制降低了父系表达基因10（PEG10）的水平，导致滋养层细胞侵袭受损。此外，由自噬抑制的滋养层细胞培养的NK细胞进一步降低了滋养层细胞的增殖和侵袭性。在妊娠小鼠模型中，注射3-MA可促进子宫NK细胞的细胞毒性，并增加胚胎吸收率。结论 滋养层细胞自噬抑制增加了NK细胞的细胞毒性，并可能通过分别靶向IGF-2和PEG10来损害滋养层细胞的侵袭，最终导致流产。视频摘要。