Macrophages, fibrosis, and intrauterine adhesions: Cellular interactions and pathophysiological implications

Intrauterine Adhesion (IUA) is a pathological condition caused by damage to the basal layer of the endometrium, often triggered by uterine surgeries such as curettage or intrauterine infections. It is primarily characterized that the normal endometrial tissue is replaced by intrauterine fibrosis and adhesion formation, leading to menorrhagia, amenorrhea, infertility, and recurrent pregnancy loss. Emerging evidence underscores macrophages as central orchestrators of fibrotic progression in IUA, modulating cytokine cascades (e.g., TGF-β/Smad) and ECM remodeling through dynamic polarization shifts (M1/M2). In the early stages of IUA, M1 macrophages are activated by pro-inflammatory signals and secrete cytokines such as TNF-α and IL-1β. These factors amplify the inflammatory response, aggravate tissue damage, and impede endometrial repair. Conversely, during the repair phase, M2 macrophages are activated in response to anti-inflammatory signals. M2 macrophages secrete TGF-β, IL-10, and other pro-repair mediators, which promote fibroblast activation and their myofibroblast transdifferentiation, key cells responsible for ECM production. However, overactivation of M2 macrophages and excessive production of TGF-β result in uncontrolled ECM accumulation, driving progressive fibrosis and adhesion formation. This review aims to explore the mechanistic link between macrophage activation and fibrotic pathways in IUA. Emerging therapeutic strategies targeting macrophage plasticity including nanoparticle-mediated polarization modulation and cytokine axis inhibition, offer promising avenues for reducing fibrosis and improving clinical outcomes in patients with IUA.