Role of HMGB1/RAGE axis in endometrial repair: evidence from the Rat Model of Induced Menstruation

Menstruation in humans involves a sequelae of inflammatory events. Endometrial repair occurs concomitantly with breakdown of endometrium. Menstrual fluid (MF) components are known to promote endometrial repair. High Mobility Group Box−1 (HMGB1) protein has been identified in MF and has implications in wound repair in several cell types. Current study was undertaken to explore whether HMGB1 plays a role in endometrial repair. Toward this, a Rat Model of Induced Menstruation (RMIM) was employed. The model demonstrated a complete endometrial breakdown at 24 hrs (T24, n=7 rats) and complete endometrial repair at 48 hrs (T48, n=7 rats), post-progesterone withdrawal. Immunofluorescence was performed to evaluate the relative presence of various proteins in endometrium. A significant increase in staining intensities (p<0.001) and secretion (p<0.05) of HMGB1 was observed in endometrium, at 8 hrs post-progesterone withdrawal (T8). Also, staining intensities of HMGB1’s receptor, Receptor for Advanced Glycation End Products (RAGE) increased significantly (p<0.001) at T8. Intensities of nuclear factor kappa-B (NF-κB) and vascular endothelial growth factor (VEGF) staining, and recruitment of macrophages in the endometrium peaked at T24. Inhibiting HMGB1/RAGE axis at T0 and T24 delayed the endometrial repair at T48 in 87% of RMIMs (n=8 rats). Moreover, inhibiting the axis at T24 completely impeded endometrial re-epithelialization in 75% of RMIMs (n=8 rats) at T48. HMGB1/RAGE axis inhibition reduced the staining intensities of NF-κB and VEGF and reduced macrophage recruitment of in endometrium. This study provides initial evidence that extracellular HMGB1 released by degrading endometrium plays a role in the endometrial repair via RAGE. In brief Endometrial repair occurs concurrently with breakdown in the absence of steroid hormones. This study investigated the role of High Mobility Group Box1 (HMGB1) as an alarmin, released during endometrial breakdown, in endometrial repair through its receptor RAGE.