Rapamycin prevents spontaneous abortion by triggering decidual stromal cell autophagy-mediated NK cell residence

Abstract

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.

Autophagy Process in Trophoblast Cells Invasion and Differentiation: Similitude and Differences With Cancer Cells

“…It has been described that autophagy is highly activated in decidualized endometrium of early pregnancy, which increases NK cell adhesion and retention in the decidua. Also, when autophagy is inhibited, decidual NK (dNK) cell residence is decreased, contributing to spontaneous abortion (171). Tan et al described that autophagy levels are highly reduced in cases of recurrent miscarriage.…”

Essential Role of CRIM1 on Endometrial Receptivity in Goat

“…Autophagy is hormonally regulated in the endometrium and plays essential roles in physiological and pathological processes [ 55 ]. Additionally, autophagy is involved in energetic metabolism via recycling metabolites to promote the survival of EECs and trophoblasts under low oxygen and low nutrient conditions of the maternal–fetal interface [ 56 ]. Toschi et al reported that the autophagy pathway is required for vasculogensis and placental development during early pregnancy in sheep [ 57 ].…”

Ovarian hormones-autophagy-immunity axis in menstruation and endometriosis

“…These characteristics of uNK cells are likely to prevent microbial infections 77 . Our recent studies demonstrated that the increase of autophagy of ESCs should promote the residence of NK cells in endometrium/decidua through upregulating MMP-9 and adhesion molecules expression 87 . Therefore, the increased numbers of resident uNK cell in the endometrium, triggered by high levels of autophagy during menstruation, supports immune defense.…”

“…In addition, autophagy induces G0/G1 arrest and apoptosis in menstrual blood-derived endometrial stem cells 97 . Autophagy of ESC promotes the upregulation of MMP9 in a melanocyte inducing transcription factor (MITF)- herpesvirus entry mediator (HVEM)-dependent manner 87 , resulting in rapid ECM degradation and endometrial exfoliation occur during menstruation. Remarkably, the intracellular composition of the ESC can be renewed through autophagy.…”

“…Several synthetic autophagy modulators have been identified as promising candidates for the treatment of cancers or benign lesions 158 . Notably, rapamycin has been shown to protect spontaneous miscarriage by inducing decidual stromal cell autophagy-mediated decidual NK cell residence 87 . Similarly, PPD also has therapeutic potential in endometriosis and UCEC by inducing cell autophagy 27 , 38 .…”