HMGB1 induces macrophage pyroptosis in chronic endometritis

Background: Chronic endometritis (CE) reflects the local imbalance in the endometrial immune microenviron-ment after inflammation. High mobility group box 1 (HMGB1) is highly involved in both immunity and inflammation. In this study, we aimed to explore the roles of HMGB1 in the endometrium of patients with CE.Methods: Endometrium and uterine fluid HMGB1 were tested in a cohort of infertile patients with or without CE. Expression levels of the pyroptosis marker, gasdermin D (GSDMD)-N-terminal (NT), in the human endometrium of patients with CE and controls were determined. Next, the role of HMGB1 as a driver of macrophage pyroptosis was investigated using human THP-1 cells in vitro and a CE mouse model in vivo.Results: High expression levels of HMGB1 in biopsied endometrial tissue and uterine fluid were confirmed in a cohort of patients with CE. Positive correlation between the number of CD138+ cells and HMGB1 mRNA expression level were detected (rs = 0.592, P < 0.001). Meanwhile, we found that GSDMD-NT expression was significantly increased in the CE endometrium at both the transcriptional and translational levels. Moreover, co-localization of GSDMD-NT and macrophages was confirmed via the double immunostaining of GSDMD-NT and CD68. In vitro experiments revealed that macrophage pyroptosis was induced by HMGB1 in human THP-1-derived macrophages. Treatment with glycyrrhizic acid, an inhibitor of HMGB1, significantly suppressed endometrial pyroptosis and inflammation in the CE mouse model.Conclusions: HMGB1 effectively induced macrophage pyroptosis in the human endometrium, suggesting that its inhibition may serve as a novel treatment option for CE.