C5aR1+ macrophages are involved in the progression of endometriosis

Objective: Immune dysfunction plays an important role in the pathogenesis of endometriosis. C5a, a by-product of complement activation, binds to its receptor (C5a receptor 1, C5aR1) in various cells, including macrophages. The combination of C5a and C5aR1 in macrophages induces M2 polarization. There is no consistent conclusion regarding macrophage polarization status and its participation in the pathogenesis of endometriosis. Methods: We analyzed the expression of C5aR1 and the immunophenotype of macrophages in samples from patients with endometriosis using immunohistochemistry and flow cytometry. We tested the equivalent item in a mouse model and the THP-1 cell line in vivo and in vitro . Single-cell RNA sequencing (scRNA-seq) from the Gene Expression Omnibus (GEO, GSE213216) was used to investigate the phenotype and function of C5aR1 + macrophages. Results: The infiltration of C5aR1 + macrophages was associated with the severity of endometriosis. C5aR1 + macrophages polarized more toward the M2 phenotype and transformed into an immunosuppressive state. Inhibiting C5aR1 using PMX-53 decreased the expression of C5aR1 + macrophages and reduced their polarization to the M2 phenotype, consequently shrinking lesion size in a mouse model. Conclusion: Our study emphasizes the importance of C5aR1 and the macrophage phenotype in the pathogenesis of endometriosis. We propose PMX-53 as a potential therapeutic agent for endometriosis.