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

TL;DR

This study finds that IL-37 reduces chronic endometritis by blocking tissue changes and encouraging anti-inflammatory immune cells.

Contribution

The novel contribution is identifying IL-37's role in suppressing EMT and promoting M2 macrophage polarization in chronic endometritis.

Findings

IL-37 reduces epithelial-mesenchymal transition by upregulating E-cadherin and downregulating vimentin.

IL-37 promotes M2 macrophage polarization and suppresses M1 infiltration in chronic endometritis.

The STAT6 and Smad3 pathways are coactivated by IL-37 to mitigate inflammation and tissue damage.

Abstract

Interleukin-37 (IL-37) is an anti-inflammatory cytokine with an undefined role in chronic endometritis (CE). This study aims to explore its therapeutic mechanism in CE, focusing on epithelial-mesenchymal transition (EMT) and macrophage polarization. A CE model was induced in Sprague-Dawley rats using lipopolysaccharide (LPS), followed by intervention with TAT-fused recombinant IL-37. Histological damage and fibrosis were evaluated through H&E and Masson staining. Immunofluorescence staining was performed to assess the expression of IL-37 and EMT markers (E-cadherin and vimentin) and macrophage phenotypes (M1: CD86+; M2: CD206+). In vitro, transwell, qPCR, Western blot, and flow cytometry analyses were performed to determine the effects of IL-37 on EMT and macrophage polarization. The activity of the STAT6 and Smad3 pathways was evaluated using Western blotting, dual-luciferase assays, and immunofluorescence staining. The results revealed that IL-37 accumulated in the injured uterus, alleviating inflammation, tissue damage, and collagen deposition. IL-37 reduced epithelial migration and reversed abnormal EMT by upregulating E-cadherin expression and downregulating vimentin expression. It also suppressed M1 macrophage infiltration and promoted M2 polarization. Mechanistically, IL-37 coactivated the STAT6 and Smad3 pathways, thereby increasing their phosphorylation and nuclear translocation and elevating 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.

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