Investigating phenotypic heterogeneity of peritoneal macrophages in endometriosis

Endometriosis is a complex gynaecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to chronic pelvic pain, infertility, and other debilitating symptoms. Despite its prevalence and significant impact on women's health and quality of life, the pathogenesis of endometriosis remains poorly understood. Macrophages play a pivotal role in the pathophysiology of endometriosis; yet our understanding of the immune landscape within the human peritoneal cavity is limited. However, two macrophage population of distinct origin are known. Monocyte-derived (Timd4-) large peritoneal macrophages (LpM) that have a protective, endometriosis-limiting phenotype and embryo-derived (Timd4+) LpMs that are disease-permissive. In this study, two experimental mouse models of endometriosis were used, and the peritoneal fluid was sequenced by scRNA-seq. Through GO analysis, it appeared that the monocyte-derived LpM were protective because of increased phagocytic function, but the results from this were not conclusive. Another highlighted potential mechanism was by restricting the accessibility of cholesterol, which serves as a potential energy source for lesion proliferation. To investigate if findings from the mouse models could be translated into humans, a cross-species analysis was done. This analysis unveiled two distinct populations of peritoneal macrophages, VCAN+ and LYVE+ peritoneal macrophages, exclusively identified in the human data set but absent in the Endo-Intact mouse model. These populations exhibited phenotypes conducive to proliferation and invasion, akin to tumour-associated macrophages (TAMs). Given the pivotal role of peritoneal macrophages in endometriosis pathogenesis, this research is important in identify and characterising the pro-disease macrophage populations in humans is imperative to the development of efficacious immunomodulating therapies to treat this debilitating disorder.