Targeting the IL-17C-M2 macrophage axis ameliorates fibrosis in endometriosis through MAPK/ERK signaling

Endometriosis is characterized by inflammation and fibrosis, in which cytokines and cytokine-macrophage interactions serve as critical mediators. However, the specific mechanisms that initiate the fibrotic cascade in endometriosis remain poorly defined.

Spatial transcriptomics (ST) and cellular interaction analyses were performed on human specimens of endometriotic lesions and normal endometrium. An endometriosis mouse model was used to evaluate the effect of IL-17 C neutralization with the MOR106 antibody on ectopic lesion growth and fibrosis. In vitro experiments were conducted to explore the role of IL-17 C in macrophage polarization and extracellular matrix (ECM) production by endometrial stromal cells (ESCs).

IL-17RE expression was significantly upregulated in endometriotic tissues compared with normal endometrium and correlated with endometriosis fibrosis. IL-17 C levels were markedly higher in patient-derived tissues and peritoneal fluid. In a mouse model of endometriosis, neutralization of IL-17 C with the MOR106 antibody inhibited ectopic lesion growth and alleviated fibrosis in both eutopic and ectopic endometrium. Importantly, MOR106 selectively reduced CD206 + M2 macrophage infiltration in lesions without significantly altering the M1 macrophage population, suggesting that IL-17 C primarily drives M2-like macrophage accumulation in vivo. In vitro, IL-17 C promoted macrophage polarization toward a pro-fibrotic M2-like phenotype, and these IL-17 C-induced M2 macrophages enhanced ECM production by ESCs via activation of the MAPK/ERK pathway.

Targeting the IL-17 C/IL-17RE axis provides a promising novel therapeutic strategy for mitigating fibrosis in endometriosis.