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

Han Lu; Hui-Li Yang; Wen-Jie Zhou; Zhen-Zhen Lai; Xue-Min Qiu; Qiang Fu; Jian-Yuan Zhao; Jian Wang; Da-Jin Li; Ming-Qing Li

doi:10.1080/15548627.2020.1833515

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

Autophagy. 2021 Sep;17(9):2511-2527. doi: 10.1080/15548627.2020.1833515. Epub 2020 Nov 1.

Authors

Han Lu^{1

2}, Hui-Li Yang^{2

3}, Wen-Jie Zhou⁴, Zhen-Zhen Lai², Xue-Min Qiu^{2

3}, Qiang Fu⁵, Jian-Yuan Zhao^{6

7}, Jian Wang¹, Da-Jin Li^{1

2}, Ming-Qing Li^{1

2

3}

Affiliations

¹ NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People's Republic of China.
² Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People's Republic of China.
³ Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People's Republic of China.
⁴ Center of Reproductive Medicine of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
⁵ Department of Immunology, Binzhou Medical College, Yantai, People's Republic of China.
⁶ State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, People's Republic of China.
⁷ Institute of Metabolism and Integrative Biology (IMIB), School of Life Sciences, Fudan University, Shanghai, People's Republic of China.

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.Abbreviations: ACTA2/αSMA: actin alpha 2, smooth muscle; ATG: autophagy-related; ATG5^over ESC: ATG5-overexpressed ESCs; BTLA: B and T lymphocyte associated; CDH1: cadherin 1; CDH5: cadherin 5; CXCL12: C-X-C motif chemokine ligand 12; dNK: decidual NK; DIC: decidual immune cell; DSC: decidual stromal cell; EOMES: eomesodermin; ESC: endometrial stromal cell; FCGR3A/CD16: Fc fragment of IgG receptor IIIa; HUVEC: human umbilical vein endothelial cell; ICAM: intercellular cell adhesion molecule; ILC: innate lymphoid cell; ITGB1: integrin subunit beta 1; ITGA2: integrin subunit alpha 2; IPA: Ingenuity Pathway Analysis; KIR2DL1: killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1; KLRD1/CD94: killer cell lectin like receptor D1; KLRK1/NKG2D: killer cell lectin like receptor K1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; 3-MA: 3-methyladenine; MITF: melanocyte inducing transcription factor; MiT-TFE: microphthalmia family of bHLH-LZ transcription factors; MMP9: matrix metalloproteinase 9; MTOR: mechanistic target of rapamycin kinase; NCAM1/CD56: neural cell adhesion molecule 1; NCR2/NKp44: natural cytotoxicity triggering receptor 2; NK: natural killer; KLRB1/NK1.1: killer cell lectin like receptor B1; NP: normal pregnancy; PBMC: peripheral blood mononuclear cell; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; pNK: peripheral blood NK; PRF1/Perforin: Perforin 1; PTPRC/CD45: protein tyrosine phosphatase receptor type C; Rapa: rapamycin; rh-TNFSF14/LIGHT: recombinant human TNFSF14/LIGHT; SA: spontaneous abortion; SELE: selectin E; SELP: selectin P; SELL: selectin L; siATG5 DSCs: ATG5-silenced DSCs; siTNFRSF14/HVEM DSCs: TNFRSF14/HVEM-silenced DSCs; TBX21/T-bet: T-box transcription factor 21; SQSTM1/p62: sequestosome 1; TNFRSF14/HVEM: TNF receptor superfamily member 14; TNFSF14/LIGHT: TNF superfamily member 14; uNK: uterine NK; UIC: uterine immune cell; USC: uterine stromal cell; VCAM1: vascular cell adhesion molecule 1; VIM: vimentin.

Keywords: Autophagy; MITF; MMP9; NK cells; TNFRSF14/HVEM; abortion; decidual stromal cells; early pregnancy; residence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abortion, Spontaneous* / metabolism
Animals
Autophagy*
Female
Humans
Immunity, Innate
Killer Cells, Natural* / cytology
Leukocytes, Mononuclear
Mice
Pregnancy
Sirolimus* / pharmacology
Stromal Cells* / cytology

Substances

Sirolimus

Grants and funding

This study was supported by the National Natural Science Foundation of China (NSFC) [No. 31970798, 31671200, 82001636, 81901563 and 81571512]; the National Key Research and Development Program of China [2017YFC1001404]; the Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation [CX2017-2]; and the Program for Zhuoxue of Fudan University [JIF157602].