MTA1-mediated transcriptional repression of Cox2 confers resistance against neutrophil infiltration in endometritis.

Abnormal accumulation of prostaglandin E2 (PGE2) is a secondary effect of the presence of bacterial infection, and usually causes overproduction of proinflammatory cytokines, thereby leading to infiltration of neutrophils, serving as a key etiology of endometritis linking to infertility. Metastasis-associated protein 1 (MTA1), functioning as a master transcriptional coregulator, is increasingly recognized as an important influencer of inflammation, but its functional roles in endometritis, if any, remain unexplored. Herein, by investigating clinical correlations, in vitro assays, and uterus-specific Mta1 knockouts, we show that MTA1 expression was significantly downregulated in endometrial biopsies from patients with chronic endometritis (CE) and in human endometrial stromal cells (HESCs) challenged with clinically relevant pathogenic dosage of lipopolysaccharide (LPS). MTA1 deletion augmented endometrial neutrophil infiltration, exacerbated inflammatory phenotype and negatively affected the outcome of LPS-induced endometritis through modulation of PGE2 secretion. We have also identified cyclooxygenase-2 (COX2) as the key rate-limiting enzyme responsible for the deregulated PGE2 synthesis in MTA1 deficiency-exacerbated endometritis. Mechanistically, MTA1 negatively regulated the transcription of Cox2, likely in collaboration with HDAC2 (histone deacetylase 2), in LPS-challenged endometrial stromal cells (ESCs). In summary, MTA1 signaling may govern appropriate inflammatory response in ESCs against the pathogenesis of endometritis.