Targeting TET3 in macrophages provides a concept strategy for the treatment of endometriosis

Abstract

Endometriosis, characterized by the presence of endometrial-like tissue outside the uterus, is a condition associated with pain and infertility. In this issue of the JCI, Lv et al. illuminate the critical pathophysiological role of the ten-eleven translocation 3 (TET3) in endometriosis. TET3 expression levels were higher in macrophages of endometriotic lesions compared with control endometrial tissue, implicating TET3 as a contributing factor in the chronic inflammation that occurs in endometriosis. TGF-β1 and MCP1 are present in the peritoneal cavity of women with endometriosis, and macrophage exposure to these factors resulted in upregulation of TET3, thereby promoting their survival. Notably, Bobcat339, a selective TET inhibitor, induced apoptosis in these macrophages. Further, myeloid-specific TET3 loss reduced endometriosis in mice. RNA-Seq analysis following TET3 knockdown revealed alterations in cytokine signaling and cell-death pathways, underscoring the therapeutic potential of targeting TET3 in macrophages as a strategy for managing endometriosis.

Figure 1. Macrophage-expressed TET3 has a pathophysiological role in endometriosis.

In a healthy uterine environment, antiinflammatory, repair macrophages produce interleukins and interferons that maintain healthy tissue. In contrast, inflammatory macrophages associated with endometriotic lesions express increased TET3 levels. The endometriosis environment has increased levels of TGF-β1 and MCP1, both of which can induce TET3 expression in macrophages. TET3 blocks the posttranscriptional miRNA regulator let-7, resulting in increased production and secretion of the proinflammatory cytokines IL-6 and IL-1β. TET3 also interacts with the STAT3/NCOR1/HDAC4 transcriptional corepressor complex to exert additional inflammatory effects.