Dataset Information

Deficiency of MST1 in endometriosis related peritoneal macrophages promoted the autophagy of ectopic endometrial stromal cells by IL-10.

ABSTRACT: Changes in the function of peritoneal macrophages contribute to the homeostasis of the peritoneal immune microenvironment in endometriosis. The mechanism by which ectopic tissues escape phagocytic clearance by macrophages to achieve ectopic colonization and proliferation is unknown. The expression of CD163 in peritoneal macrophages in patients with endometriosis is increased, with the overexpression of MAPK, which can promote the M2-type polarization of macrophages and reduce their ability to phagocytose ectopic endometrial cells. As an upstream regulator of MAPK, MST1 expression is deficient in peritoneal macrophages of patients with endometriosis. This process is regulated by miR-887-5p, a noncoding RNA targeting MST1. Moreover, MST1-knockout macrophages secrete anti-inflammatory factor IL-10, which promotes autophagy of ectopic endometrial stromal cells. These results suggest that MST1 deficient macrophages may accelerate the autophagy of ectopic endometrium via IL-10 which was regulated by miR-887-5p.

SUBMITTER: Huang Y

PROVIDER: S-EPMC9575673 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Deficiency of <i>MST1</i> in endometriosis related peritoneal macrophages promoted the autophagy of ectopic endometrial stromal cells by IL-10.

Huang Yufei Y Yan Shumin S Dong Xiaoyu X Jiao Xue X Wang Shuang S Li Dong D Wang Guoyun G

Frontiers in immunology 20221003

Changes in the function of peritoneal macrophages contribute to the homeostasis of the peritoneal immune microenvironment in endometriosis. The mechanism by which ectopic tissues escape phagocytic clearance by macrophages to achieve ectopic colonization and proliferation is unknown. The expression of CD163 in peritoneal macrophages in patients with endometriosis is increased, with the overexpression of <i>MAPK</i>, which can promote the M2-type polarization of macrophages and reduce their abilit ...[more]

PMID: 36263059

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Project description:Endometriosis (EMs) is a common infertility-related disease in women of reproductive age. Impaired endometrial decidualization is one of the most important factors contributing to the embryo implantation failure EMs patients. However, the exact mechanism remains unclear. Previous studies have shown collagen I deposition in the eutopic endometrium of EMs patients, which may lead to impaired endometrial decidualization. The level of collagen I in eutopic endometrium of EMs was analyzed. We performed a proteomic analysis of ectopic endometrial stromal cell-derived extracellular vesicles (EMs-EVs) and extracellular vesicles derived from endometrial stromal cells in the endometrium of control patients (CTL-EVs). An endometrial transcriptional profiles of EMs patients and normal controls in the mid-secretory phase of menstrual cycle was compared. Endometrial stromal cells (ESCs) were stimulated with chloroquine or rapamycin to evaluate the association between autophagy and collagen I. The expression of PKM2 in EMs-EVs and serum extracellular vesicles from EMs patients were examined by western blotting. PKM2 was overexpressed or knockdown in ESCs to investigate the level of autophagy and collagen I. ESCs were treated with ectopic ESC-derived extracellular vesicles with highly expressed PKM2 protein, and the potential molecular mechanisms were further confirmed through western blotting and immunohistochemical analysis. We found that endometrial collagen I expression during the mid-secretory phase was increased in the EMs group. We demonstrated that autophagy is defective in eutopic endometrial stromal cells (ESCs) of EMs patients. In ESCs, pharmacological inhibition of autophagy by chloroquine (CQ) promoted collagen I deposition. Ectopic endometrial stromal cell-derived extracellular vesicles (EMs-EVs) inhibited autophagy of ESCs and promoted collagen I deposition in vivo and in vitro. Mechanistically, EMs-EVs encapsulating PKM2 impair eutopic endometrial autophagy via Akt/mTOR signaling pathway. Together, we demonstrated that EMs-EVs encapsulating PKM2 impaired endometrial autophagy inducing collagen I deposition in EMs, which provided a potential target for therapeutic implications.

Project description:BackgroundAs a dual-function metabolite, succinate has emerged in cell function and plays a key signaling role in linking mitochondrial function to other cellular functions. Succinate accumulation in the cytoplasm is commonly associated with hypoxia in the microenvironment and immune cell activation. Extracellular succinate released into the microenvironment is considered an inflammatory alarm that can be sensed by its membrane receptor SUCNR1, which boosts proinflammatory responses and acts akin to classical hormones and cytokines. Succinate plays an important role in the development of inflammatory diseases. Whether succinate facilitates the progression of endometriosis (EMs), characterized by chronic inflammation and peritoneal adhesion, is worth exploring.ObjectiveWe mimicked the ectopic milieu in vitro and in vivo to evaluate the main source and potential role of succinate in endometriosis. We assessed the molecular and functional effects of succinate on macrophages and peritoneal mesothelial cells in peritoneal cavity. The effect of succinate/SUCNR1 signaling on ectopic endometrial stromal cells (ESCs) was further explored in this study.MethodsIn this study, we used targeted organic acid metabolomics analysis and in vitro assays to assess the potential accumulation of succinate in the peritoneal fluid of EMs patients. We examined its correlation with disease severity, Visual Analogue Scale, and the Endometriosis Fertility Index. Flow cytometry, enzyme linked immunosorbent assay, western blot assay, quantitative real-time PCR, and other molecular biology techniques were used to explore the potential mechanisms.ResultsBy mimicking the ectopic milieu, we constructed an in vitro co-culture system and found that M1 polarized macrophages and that the peritoneal mesothelial cell line (HMrSV5) mainly released succinate into their microenvironment and activated the succinate receptor (SUCNR1) signal, which further polarized the macrophages and significantly enhanced the invasive survival of ESCs, and the adhesion to the peritoneum. We further investigated the pathological effects of extracellular succinate in vivo using a xenograft mouse models of endometriosis.ConclusionsSuccinate-SUCNR1 signaling facilitates the creation of inflammatory cells and plays a vital role in EMs progression and peritoneal adhesion. Our work on the molecular mechanisms underlying succinate accumulation and function will help elucidate the phenotypic mysteries of pain and infertility in EMs. Video Abstract.

Dataset Information

Deficiency of MST1 in endometriosis related peritoneal macrophages promoted the autophagy of ectopic endometrial stromal cells by IL-10.

Publications

Deficiency of <i>MST1</i> in endometriosis related peritoneal macrophages promoted the autophagy of ectopic endometrial stromal cells by IL-10.

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