Luteolin inhibits IL-33/ST2L-induced M2 macrophage polarization in endometriosis

Endometriosis is a chronic inflammatory disease characterized by immune microenvironment dysregulation, with the IL-33/ST2L signaling axis playing a crucial role in macrophage polarization and disease progression. Despite growing evidence of IL-33's involvement in endometriosis pathogenesis, the mechanisms underlying IL-33-induced macrophage polarization and the therapeutic potential of a natural immunomodulator luteolin remain incompletely understood.

We investigated the effects of luteolin on IL-33/ST2L-mediated M2 macrophage polarization using in vitro cell culture models and an in vivo mouse endometriosis model. The proliferation and migration of human endometrial stromal cells (HESCs) were assessed following macrophage co-culture experiments. The MyD88/NF-κB signaling pathway and inflammatory cytokine expression were analyzed using Western blotting, RT-PCR, and ELISA.

IL-33 significantly promoted M2 macrophage polarization, which subsequently enhanced HESC proliferation and migration. Luteolin treatment effectively suppressed IL-33/ST2L signaling, inhibited IL-33-induced M2 macrophage polarization, and reduced HESC proliferative and migratory activities. In the mouse endometriosis model, luteolin administration decreased IL-33 secretion, prevented M2 macrophage accumulation, and downregulated the MyD88/NF-κB pathway. This resulted in significant reduction of pro-inflammatory cytokines (IL-1β, TNF-α, IL-4, and IL-13) and amelioration of the local immune microenvironment.

Our findings demonstrate that luteolin exerts therapeutic effects in endometriosis by disrupting IL-33/ST2L-mediated M2 macrophage polarization and modulating inflammatory responses. These results suggest that luteolin is a promising natural therapeutic candidate for endometriosis treatment, offering insights into immune-targeted therapeutic strategies.