Estrogen-triggered neutrophil extracellular traps fuel sterile inflammation via NKCC1

Abstract Disorders of the menstrual cycle or exposure to external pathogens lead to uterus-related diseases, such as endometrial hyperplasia (EH) and endometritis (EN). We constructed a multiomics method to compare the molecular differences between estrogen-induced hyperplastic endometrium and infection-triggered inflammatory endometrium at the single-cell level. A unique neutrophil subpopulation that expresses Estrogen Receptor 1 (ESR1) was newly identified to be involved in EH development. Distinct from the infectious state, estrogen-induced NETs were mainly a consequence of ERα binding to HMGN2. Mechanistically, NETs could bind to NKCC1 and promote imbalance of ion homeostasis in endometrial epithelial cells, leading to cell proliferation and EH. Pharmacologically, aspirin was found to inhibit NET formation and alleviated EH in a nonhuman primate model by directly acetylating at K64 and K82 of HMGN2. Collectively, this study highlights neutrophil heterogeneity in sterile inflammation or infectious inflammation, providing a novel nonhormonal treatment strategy for the patients with estrogen abnormalities.