TET3's Role in Chronic Inflammatory Diseases Unveiled

This study examined the role of a protein called TET3 in certain immune cells known as macrophages, which can contribute to disease progression in chronic inflammatory conditions such as metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. The researchers aimed to understand how TET3 affects these macrophages and whether targeting Toe-Macs could help treat these diseases.

Chronic inflammation plays a key role in many diseases, and macrophages are central to this process. By identifying TET3 as a common epigenetic regulator in disease-causing macrophages and the unique vulnerability of Toe-Macs to TET3 reduction, this research opens the door to new treatments that could specifically target Toe-Macs while sparing beneficial macrophages and potentially alleviating conditions like MASH, NSCLC, and endometriosis. This is important for the medical community and patients, as current treatment options are limited.

The researchers used a combination of advanced techniques to study macrophages, including single-cell RNA sequencing to analyze gene expression, immunohistochemistry to visualize cells, and experiments with mice. They specifically looked at how TET3 influences macrophage behavior and tested the effects of reducing TET3 expression in them using genetic and pharmacological methods.

The study found that macrophages with high levels of TET3 are present in MASH, NSCLC, and endometriosis. Induced by the disease microenvironment, Toe-Macs contribute to disease progression by promoting inflammation. The researchers showed that reducing TET3 levels in these cells, either through genetic manipulation or a small molecule called Bobcat339, significantly reduced disease symptoms in mouse models.

Unlike homeostatic macrophages that are not sensitive to TET3 reduction, Toe-Macs rely on TET3 overexpression for survival and are hence vulnerable to TET3 reduction. These findings suggest that Toe-Macs could be targets for new therapies. By selectively eliminating these macrophages, it might be possible to treat various chronic inflammatory diseases more effectively. This could lead to the development of treatments that specifically target the harmful aspects of inflammation without affecting the beneficial ones

The authors propose further research to explore the exact mechanisms by which TET3 influences macrophage behavior and to develop TET3-targeted therapies for clinical use. They suggest that understanding the broader impact of TET3 on gene expression in Toe-Macs could reveal more about its role in inflammation and disease.

This research was supported by the Yale Discover to Cure Program, a Paul Titus Scholar Award, the Albert McKern Fund, the Blavatnik Family Foundation, and the National Natural Science Foundation of China (grant No. 82371647). The Yale Department of Obstetrics, Gynecology and Reproductive Sciences also provided funding and support for this research.