M2 Macrophages are Major Mediators of Germline Risk of Endometriosis and Explain Pleiotropy with Comorbid Traits

Endometriosis is a common gynecologic condition that causes chronic life-altering symptoms including pain, infertility, and elevated cancer risk. There is an urgent need for new non-hormonal targeted therapeutics to treat endometriosis, but until very recently, the cellular and molecular signatures of endometriotic lesions were undefined, severely hindering the development of clinical advances. Integrating inherited risk data from analyses of >450,000 individuals with ∼350,000 single cell transcriptomes from 21 patients, we uncover M2-macrophages as candidate drivers of disease susceptibility, and nominate IL1 signaling as a central hub impacted by germline genetic variation associated with endometriosis. Extensive functional follow-up confirmed these associations and revealed a pleiotropic role for this pathway in endometriosis. Population-scale expression quantitative trail locus analysis demonstrated that genetic variation controlling IL1A expression is also associated with endometriosis risk variants. Manipulation of IL1 signaling in state-of-the-art in vitro decidualized assembloids impacted epithelial differentiation, and in an in vivo endometriosis model, treatment with anakinra (an interleukin-1 receptor antagonist) resulted in a significant, dose-dependent reduction in both spontaneous pain and evoked pain. Together these studies highlight non-diagnostic cell types as central to endometriosis susceptibility and support IL1 signaling as an important actionable pathway for this disease.