Reproduction (Cambridge, England) · 2025
Role of HMGB1/RAGE axis in endometrial repair: evidence from the rat model of induced menstruation.
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Khandvilkar Aditya, Metkari Siddhanath, Padvi Ajay, Sachdeva Geetanjali, Chaudhari Uddhav
Аннотация
IN BRIEF: Endometrial repair occurs concurrently with breakdown in the absence of steroid hormones. This study investigated the role of high mobility group box 1 (HMGB1) as an alarmin, released during endometrial breakdown, in endometrial repair through its receptor RAGE.
ABSTRACT: Menstruation in humans involves a sequelae of inflammatory events. Endometrial repair occurs concomitantly with the breakdown of the endometrium. Menstrual fluid (MF) components are known to promote endometrial repair. HMGB1 protein has been identified in MF and has implications in wound repair in several cell types. The 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 complete endometrial breakdown at 24 h (T24, n = 7 rats) and complete endometrial repair at 48 h (T48, n = 7 rats), post-progesterone withdrawal. Immunofluorescence was performed to evaluate the relative presence of various proteins in the endometrium. A significant increase in staining intensities (P < 0.001) and secretion (P < 0.05) of HMGB1 was observed in the endometrium, at 8 h post-progesterone withdrawal (T8). In addition, staining intensities of HMGB1's receptor, the receptor for advanced glycation endproducts (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 the 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 in endometrium. This study provides initial evidence that extracellular HMGB1 released by degrading endometrium plays a role in endometrial repair via RAGE.
ABSTRACT: Menstruation in humans involves a sequelae of inflammatory events. Endometrial repair occurs concomitantly with the breakdown of the endometrium. Menstrual fluid (MF) components are known to promote endometrial repair. HMGB1 protein has been identified in MF and has implications in wound repair in several cell types. The 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 complete endometrial breakdown at 24 h (T24, n = 7 rats) and complete endometrial repair at 48 h (T48, n = 7 rats), post-progesterone withdrawal. Immunofluorescence was performed to evaluate the relative presence of various proteins in the endometrium. A significant increase in staining intensities (P < 0.001) and secretion (P < 0.05) of HMGB1 was observed in the endometrium, at 8 h post-progesterone withdrawal (T8). In addition, staining intensities of HMGB1's receptor, the receptor for advanced glycation endproducts (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 the 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 in endometrium. This study provides initial evidence that extracellular HMGB1 released by degrading endometrium plays a role in endometrial repair via RAGE.