Granzyme A Regulates Uterine Immune-Endocrine Homeostasis in the Female Reproductive Tract 2302876

Abstract Introduction The female reproductive tract (FRT) requires tightly regulated immune responses to maintain tissue homeostasis, ensure hormonal balance, and support fertility. Dysregulation of this balance contributes to infertility, chronic pelvic inflammation, and poor pregnancy outcomes. Although immune cells are known to play a central role in maintaining FRT equilibrium, the underlying mechanisms remain incompletely understood. Here, we identify granzyme A (GzmA), a serine protease predominantly produced by ovarian and uterine natural killer (NK) cells, as a key regulator of the FRT. Methods We used wild-type and GzmA-deficient female mice to assess reproductive inflammation, estrous cycle patterns, uterine and ovarian morphology, and fertility outcomes. Vaginal cytology, gross tissue measurements, immunofluorescence imaging, qPCR, flow cytometry, and breeding records were used to evaluate structural, hormonal, and immune changes associated with GzmA loss. Results Loss of GzmA resulted in marked alterations in uterine morphology, disrupted estrous cycle synchronization, and subfertility. These included increased uterine weight, shortened uterine horns, excessive mucus production, enlarged endometrium, and evidence of hormonal imbalance, features commonly associated with reproductive pathologies such as endometriosis and Polycystic Ovary Syndrome (PCOS). Notably, recent clinical studies report reduced GzmA levels in the peritoneal fluid of patients with endometriosis, aligning with our findings and supporting a role for impaired granzyme signaling in the disease. Conclusion These findings reveal a previously unrecognized role for NK cell-derived GzmA in regulating endometrial growth and preserving immune-hormonal homeostasis in the FRT and suggest that dysregulation of this pathway may contribute to female reproductive disease. Funding Source The Women’s Global Health Institute (WGHI) at Purdue University Topic Categories Mucosal and Regional Immunology (MUC)