Chronic endometritis (CE) is a persistent inflammatory disease of local endometrium caused by an abnormal endometrial microbiome (Moreno et al., 2018). The diagnosis of CE via histologic analysis for the presence of ≥ 5 CD138+ (or Syndecan-1) plasma cell infiltration in the endometrial stroma at least one high-power fields and somewhat painful endometrial biopsy was used in recent studies (Li et al., 2021, Xiong et al., 2021, Herlihy et al., 2022, Kuroda et al., 2022). CE disturbs the endometrial receptivity detriment the window of implantation (Kuroda et al., 2020), resulting in infertility, repeated implantation failure (RIF) of in vitro fertilization and unexplained recurrent abortion. Furthermore, CE destroys the immune microenvironment in endometrium, which consists of immune cells and immune molecules (Zeng et al., 2022), causing the increase of CD138+ plasma cells, CD3+ T cells, Th1 CD4+ cells, besides cytokines selection-E, IL-17, IL-1β, IL-6 and TNF-α, whereas decreased Th2 CD4+ cells and cytokines CCL4, IL10，IL-11 and TGFβ.

Antimicrobial peptides (AMPs) are the key players in the maintenance of mucosal immunity to prevent bacterial infection. The AMPs consist of many molecules such as defensins, LL-37 and lipid-carrying protein-2 (LCN2). Defensins are a family of defense peptides which play antimicrobial function in epithelial cells (Xu and Lu, 2020). Human β-defensin 1 (hBD-1) constitutively expressed at mucosal tissue to play protection functions against bacteria, virus and fungi. While hBD-2 and hBD-3 are expressed upon stimulation with microbe and pro-inflammatory cytokines in epithelial and mucosal tissues. The expression of human alpha defensins HNP1–3 expression were significantly higher in cases presenting with female factor infertility as compared with purely male factor infertility (Das et al., 2007). Topical vaginal estrogen treatment of post-menopausal women showed significant increases in the concentrations of the defensins including LCN2、SLPI、hBD-2 and hBD-3 (Stanton et al., 2020). Antimicrobial peptide LCN2 inhibited pathogenic Escherichia coli and Brucella abortus infection and survival in bladder epithelial cells (Chen et al., 2022b). However, the concentration of AMPs such as defensins and LCN2 in the chronic endometritis patients are still unclear.

It has been reported that estrogens, in particular E2，can control the proinflammatory signals of the immune system. Estrogen receptor α (ERα) modulates host innate immune response to bacterial infection and chronic inflammation through inducing or repressing the transcription of cytokines, belongs to an anti-inflammatory phenotype. It has been reported that ERα antagonist, methyl-piperidino-pyrazole (MPP) contrary of in the bladder and kidney in response to urinary tract infection (Sen et al., 2019). E2-activated ERα has been reported to regulate PI3K/AKT pathway and TNFα-NFκB signaling pathway (Cheng et al., 2021, Wang et al., 2022). Herein, we aimed to discover the signaling pathway regulated by E2-activated ERα and reveal the function related to AMPs. Stimulator of interferon genes (STING) is a membrane protein that resides in the endoplasmic reticulum and serves as an essential mediator of innate immune signaling in mammals in responses to cytosolic DNA ligands produced from pathogens (Ishikawa and Barber, 2008, Zhong et al., 2008). In addition, STING can directly sense cyclic dinucleotide, such as c-di-GMP, secreted by invading bacteria (Burdette et al., 2011, Kobayashi et al., 2015). STING can also detect mitochondrial DNA produced upon infection by certain RNA viruses to perform antiviral roles, such as ZIKA virus，Influenza A virus and Chikungunya virus (Holm et al., 2016, Liu et al., 2018, Geng et al., 2021).

In this study, we found the expression level of α-defensin hNP-1and β-defensins hBD-2, hBD-3 and hBD-4 were increased in CD138 ≥ 5 group, whereas hBD-1 and LCN2 were significantly decreased in CD138 ≥ 5 CE group. The serum estrogen and ERα expression on endometrial tissues were increased in CE patients, which contribute to hBD-2 secretion. E2-activated ERα contribute to STING expression and phosphorylation, consequently increasing LCN2 expression and contributing to the mucosal immune during chronic endometritis.