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

Area of Science:

• Gynecology
• Immunology
• Genetics

Background:

• Endometriosis is a prevalent gynecologic condition causing chronic pain, infertility, and increased cancer risk.
• Development of non-hormonal targeted therapeutics is hindered by undefined cellular and molecular signatures of endometriotic lesions.

Purpose of the Study:

• To identify cellular and molecular drivers of endometriosis susceptibility.
• To investigate the role of IL1 signaling in endometriosis pathogenesis.
• To evaluate anakinra as a potential therapeutic for endometriosis-associated pain.

Main Methods:

• Integrated analysis of >450,000 individuals' inherited risk data with ∼350,000 single-cell transcriptomes from 21 patients.
• Functional follow-up studies, including population-scale expression quantitative trait locus analysis.
• In vitro decidualized assembloids and in vivo endometriosis models were used to assess IL1 signaling and anakinra efficacy.

Main Results:

• M2-macrophages identified as candidate drivers of endometriosis susceptibility.
• IL1 signaling nominated as a central hub impacted by germline genetic variation.
• Genetic variation controlling IL1A expression associated with endometriosis risk.
• Anakinra treatment significantly reduced spontaneous and evoked pain in an in vivo endometriosis model.

Conclusions:

• Non-diagnostic cell types, like M2-macrophages, are central to endometriosis susceptibility.
• IL1 signaling represents a critical and actionable therapeutic pathway for endometriosis.
• Anakinra demonstrates potential as a novel non-hormonal treatment for endometriosis pain.