Department of Gynecology of Integrated Traditional Chinese and Western Medicine, Hospital of Obstetrics and Gynecology, Fudan University, Shen Yang Road 128, Shanghai, 200090, People's Republic of China.
NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Pingliang Road, Shanghai, 200080, People's Republic of China.
Cell Commun Signal. 2020 May 12;18(1):73. doi: 10.1186/s12964-020-00579-w.
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.
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.
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.
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.
滋养细胞与蜕膜自然杀伤（NK）细胞之间的串扰在正常妊娠的建立和维持中起着重要作用。最近的研究报道，自噬可以在母体胎儿界面诱导免疫耐受，但其机制尚不清楚。
通过透射电子显微镜检测正常和复发性自然流产（RSA）患者绒毛中的自噬水平。用 3-甲基腺嘌呤（3-MA）或雷帕霉素预处理滋养细胞后，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细胞的侵袭能力。
与选择性妊娠终止患者相比，RSA 患者绒毛中的自噬水平显著降低。用雷帕霉素诱导滋养细胞自噬水平可显著抑制共培养体系中 NK 细胞的细胞毒性，补充 IGF-2 可纠正这种效应。同时，滋养细胞自噬抑制降低了父系表达基因 10（PEG10）的水平，导致滋养细胞侵袭能力受损。此外，经自噬抑制滋养细胞诱导的 NK 细胞进一步降低了滋养细胞的增殖和侵袭能力。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。
滋养细胞自噬抑制通过靶向 IGF-2 和 PEG10 分别增加 NK 细胞的细胞毒性并破坏滋养细胞侵袭，最终导致流产。
