Rapamycin prevents spontaneous abortion by triggering decidual stromal cell autophagy-mediated NK cell residence
Rapamycin prevents spontaneous abortion by triggering decidual stromal cell autophagy-mediated NK cell residence
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雷帕霉素通过触发蜕膜基质细胞自噬介导的 NK 细胞驻留来预防自然流产。
DOI：
10.1080/15548627.2020.1833515
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发表时间：
2020-11-02
期刊：
影响因子：
13.3
通讯作者：
Li, Ming-Qing
中科院分区：
文献类型：
--
作者：
Lu, Han;Yang, Hui-Li;Li, Ming-Qing
蜕膜化不足被广泛认为是自然流产的重要原因。广泛性蜕膜化还包括NK细胞的大量渗透和浓缩。然而，蜕膜NK(DNK)细胞滞留的潜在机制在很大程度上仍不清楚。在这里，我们观察到蜕膜间质细胞(DSCs)在蜕膜化过程中巨噬/自噬的增加，促进了DNK细胞在正常妊娠期间的黏附和保留。从机制上讲，这一过程是通过激活MITF-TNFRSF14/HVEM信号通路，并以MMP9依赖的方式进一步上调多种黏附分子(如选择素和ICAM)来实现的。原因不明的自然流产患者DSC自噬和DNK细胞滞留不足。此外，NK细胞耗竭小鼠胎盘血管重塑差，着床数少，胚胎损失率高。在治疗研究中，低剂量的雷帕霉素，一种已知的自噬诱导剂，显著促进子宫内膜自噬和NK细胞停留，并改善自然流产小鼠模型的胚胎吸收，这应该依赖于MITF-TNFRSF14/hVEM-MMP9-黏附分子轴的激活。这一观察揭示了DSCs自噬驱动的DNK细胞滞留的新的分子机制，并为预防自发流产提供了一种潜在的治疗策略。
Deficiency in decidualization has been widely regarded as an important cause of spontaneous abortion. Generalized decidualization also includes massive infiltration and enrichment of NK cells. However, the underlying mechanism of decidual NK (dNK) cell residence remains largely unknown. Here, we observe that the increased macroautophagy/autophagy of decidual stromal cells (DSCs) during decidualization, facilitates the adhesion and retention of dNK cells during normal pregnancy. Mechanistically, this process is mediated through activation of the MITF-TNFRSF14/HVEM signaling, and further upregulation of multiple adhesion adhesions (e.g. Selectins and ICAMs) in a MMP9-dependent manner. Patients with unexplained spontaneous abortion display insufficient DSC autophagy and dNK cell residence. In addition, poor vascular remodeling of placenta, low implantation number and high ratio of embryo loss are observed in NK cell depletion mice. In therapeutic studies, low doses of rapamycin, a known autophagy inducer that significantly promotes endometrium autophagy and NK cell residence, and improves embryo absorption in spontaneous abortion mice models, which should be dependent on the activation of MITF-TNFRSF14/HVEM-MMP9-adhension molecules axis. This observation reveals novel molecular mechanisms underlying DSCs autophagy-driven dNK cell residence, and provides a potential therapeutic strategy to prevent spontaneous abortion.