Hypoxia-hindered methylation of PTGIS in endometrial stromal cells accelerates endometriosis progression by inducing CD16- NK-cell differentiation

Haiyan Peng, Lichun Weng, Shating Lei, Shuhui Hou, Shaoliang Yang, Shao‐Liang Yang, Mingqing Li, Ming‐Qing Li, Dong Zhao
Experimental & molecular medicine · 2022 · vol. 54(7) , pp. 890–905 · doi:10.1038/s12276-022-00793-1 · PMID:35781537 · PMC9356144 · W4283790456
article OA: gold CC0 ⤵ 6 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Hypoxia hinders PTGIS methylation in endometrial stromal cells, increasing PGI2 and promoting endometriosis by inducing CD16− NK-cell differentiation.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

This study examined how hypoxia and epigenetic regulation of prostacyclin synthase (PTGIS) in endometrial stromal cells affect immune microenvironment changes that drive endometriosis progression. Using patient-derived endometrial stromal cells and peritoneal fluid samples, in vitro hypoxia experiments, and coculture assays with NK cells, the authors found that hypoxia promoted PTGIS expression via DNMT1-associated promoter methylation deficiency, and that PTGIS overexpression increased prostacyclin (PGI2) production and ESC adhesion while PGI2 induced CD16− NK-cell differentiation through the PTGIR receptor. In a rodent endometriosis-like model, iloprost treatment and adoptive transfer of fcgr3−/− NK cells aggravated lesion progression, whereas genetic ablation of ptgis in ectopic lesions and PTGIR antagonist treatment partially rescued outcomes. The paper’s principal limitation is that mechanistic and therapeutic conclusions are tested primarily in cell and mouse models and with defined pharmacologic/genetic perturbations rather than broader clinical validation. This paper is centrally about endometriosis — it identifies a hypoxia–PTGIS/PGI2 axis in stromal cells that promotes CD16− NK-cell differentiation and accelerates endometriosis progression.

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Abstract

Prostacyclin (PGI2) plays key roles in shaping the immune microenvironment and modulating vasodilation, whereas its contribution to endometriosis (EMs) remains largely unclear. Our study suggested that prostacyclin synthase (PTGIS)-dependent PGI2 signaling was significantly activated in EMs, which was involved in the hypoxic microenvironment of ectopic lesions and deficient methylation status of the PTGIS promoter. Notably, in vitro assays, hypoxia promoted PTGIS expression through DNA methyltransferase 1 (DNMT1)-mediated DNA methylation deficiency in endometrial stromal cells (ESCs); PTGIS overexpression enhanced the adhesive ability of ESCs and led to elevated PGI2 production, and PGI2 triggered CD16- (encoded by FCGR3, Fc fragment of IgG receptor IIIa) natural killer (NK)-cell differentiation through PGI2 receptor (IP, PTGIR) in an ESC/NK-cell coculture system. Our rodent model experiment suggested that treatment with the PGI2 analog iloprost and adoptive transfer of fcgr3 knockout (fcgr3-/-) NK cells aggravated EMs progression and that genetic ablation of ptgis (ptgis-/-) in ectopic lesions and treatment with the PTGIR antagonist RO1138452 partially rescued this outcome. Thus, our findings identified the contribution of PGI2 to EMs progression via enhancement of the adhesive ability of ESCs and inhibition of the activity of NK cells. We hypothesized that PGI2 is a target for EMs intervention and provide a rationale for studying pharmacological PTGIR inhibition and PTGIS genetic depletion therapies as therapeutic strategies for EMs.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

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