RNA-Seq analysis revealed that TET3 knockdown particularly changed pathways related to cytokine/chemokine signaling and cell death. There was an upregulation of proapoptotic genes such as Bcl2l11, Bid, and Pmaip1 alongside alterations in genes involved in inflammatory responses. Notably, the modulation of IL-6 expression in response to TET3 levels underscores its impact on macrophage function and inflammation (3). IL-6 is crucial for macrophage polarization and survival, influencing the broader inflammatory landscape of endometriosis (5, 6). Elevated IL-6 levels are often associated with increased macrophage activity and chronic inflammation, further linking TET3 with disease pathology. The interplay between TET3 and IL-6 suggests that TET3-overexpressing macrophages may drive the inflammatory response in endometriosis by modulating IL-6 signaling (Figure 1). Understanding this relationship provides insight into how TET3 contributes to the disease’s inflammatory environment and highlights potential therapeutic targets.

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.

TET enzymes, particularly TET3, play a crucial role in modulating the gene-expression profiles of macrophages through their epigenetic modifications. This capability enables macrophages to rapidly adapt to changes in their environment, a vital function given their role in immune responses (7). Unlike other cell types, macrophages exhibit remarkable plasticity, allowing them to continuously adjust their functional states between proinflammatory and antiinflammatory phenotypes in response to local stimuli. This dynamic modulation is essential for effective immune responses and tissue repair, as macrophages must respond appropriately to varying signals encountered during inflammation and injury (7). Within this context, TET3 emerges as a pivotal regulator of macrophage gene expression, underscoring its importance in the broader framework of immune adaptability.

A central component of this regulatory network is IL-6, a proinflammatory cytokine that becomes activated in chronic disease states (8). Lv et al. have shown that TET3 overexpression in macrophages leads to increased IL-6 levels, which are mediated by the inhibition of let-7 microRNAs (3). Upon stimulation, IL-6 activates the JAK/STAT3 signaling pathway, facilitating the recruitment of STAT3 to specific gene promoters, including those that regulate IL-6 and other inflammatory mediators (8, 9). This interaction enhances the transcription of genes associated with inflammation, thereby facilitating the transition of macrophages to a proinflammatory state. Moreover, TET3 has been shown to interact directly with STAT3, further complicating the regulatory mechanisms at play (10). This direct interaction suggests that TET3 may influence gene expression indirectly through IL-6 and enhance the transcriptional activity of STAT3 itself, amplifying the inflammatory response.

Thus, the interplay among TET3, IL-6, and STAT3 is vital for maintaining the balance between proinflammatory and antiinflammatory macrophage states. This balance is crucial for effective immune regulation, as dysregulation of these pathways can lead to persistent inflammation and contribute to various inflammatory diseases including endometriosis. Understanding the intricate relationships among TET3, IL-6, and STAT3 not only provides valuable insights into the molecular mechanisms underlying macrophage function, but also highlights potential therapeutic targets for modulating immune responses, offering hope for the future of immune-response modulation.