Endometriosis affects nearly one in 10 women of reproductive age and is marked by the growth of uterine-like tissue outside of the organ, causing severe pelvic pain and infertility. With no cure for endometriosis, treatments are limited to pain relivers, hormonal contraceptives and agonists, and surgery. However, these can lead to menopausal symptoms and bone density loss, and surgery has a high relapse rate. 

Despite its prevalence, endometriosis research has historically been underfunded and under-recognized, leaving its mechanisms largely unknown. Yingqun Huang, a molecular biologist at Yale School of Medicine, discussed the contributions of macrophages to the disease and how targeting specific populations of these immune cells could improve patient care.

What role do macrophages play in the pathophysiology of endometriosis?

For over a decade, researchers have recognized the role of macrophages in lesion growth, vascularization, and pain associated with the condition.¹ Recently, my colleague Hugh Taylor and I analyzed open-source single-cell RNA sequencing datasets collected from human endometriosis lesions and identified a specific population of pathogenic macrophages, characterized by overexpression of the protein TET3, which we have previously shown impacts gene regulation and is associated with various pathophysiological effects.^2,3 We showed in human and mouse in vitro models that increased expression of inflammatory cytokines caused the development of a new population of pathogenic TET3-overexpressing macrophages. This has genome-wide effects on macrophages, leading to epigenetic modifications that affect cell survival and apoptosis pathways that make these macrophages dependent on TET3 relative to normal macrophages.

How do your findings address the challenges in treating endometriosis?

To target these pathogenic macrophages, we used a synthetic small molecule that triggers protein degradation of TET3. Because the compound relies on coexpression of an enzyme that is also upregulated in these TET3-overexpressing macrophages, we had a dual cell-specific approach to target and kill this pathogenic cell population. We hope to develop this small molecule, or its derivatives, into a drug to treat endometriosis. Some clinical trials are investigating the effects of targeting these immune cells, but they focus on surface markers that are not specific to pathogenic macrophages. We think our small molecule specifically targets disease-relevant macrophages.  

Abbreviation: TET3 (tet methylcytosine dioxygenase 3).

This interview has been edited for length and clarity.