IL-37 Ameliorates Chronic Endometritis by Attenuating Epithelial-Mesenchymal Transition and Promoting M2 Macrophage Polarization

Interleukin-37 (IL-37) is an anti-inflammatory cytokine with an undefined role in chronic endometritis (CE). This study explored its therapeutic mechanism in CE, focusing on epithelial-mesenchymal transition (EMT) and macrophage polarization. A rat model of CE was induced in Sprague-Dawley rats using lipopolysaccharide (LPS), followed by intervention with recombinant IL-37. Histological damage and fibrosis were evaluated via H&E and Masson staining, while immunofluorescence localized IL-37 and assessed EMT markers (E‑cadherin, Vimentin) and macrophage phenotypes (M1: CD86⁺; M2: CD206⁺). In vitro, transwell, qPCR, Western blot, and flow cytometry analyzed IL-37’s effects on EMT and macrophage polarization. STAT6 and Smad3 pathways were examined using Western blot, dual-luciferase assays, and immunofluorescence. Results showed IL-37 accumulated in injured uterus, alleviating inflammation, tissue damage, and collagen deposition. IL-37 reduced epithelial migration and reversed abnormal EMT by upregulating E-cadherin and downregulating Vimentin. It also suppressed M1 macrophage infiltration and promoted M2 polarization. Mechanistically, IL-37 co-activated STAT6 and Smad3 pathways, enhancing their phosphorylation and nuclear translocation, thereby increasing ARG1 expression. In conclusion, IL-37 mitigates CE by suppressing EMT and promoting M2 macrophage polarization via coordinated STAT6/Smad3 activation, highlighting its therapeutic potential for CE.