Liu Beibei, Dai Yangyang, Wang Zixin, Song Jiahui, Du Yushu, Lv Haining, Bellone Stefania, Yang Yang-Hartwich, Kennedy Andrew, Zhang Songying, Venkatachalapathy Muthukumaran, Surovtseva Yulia V, Wang Penghua, Carmichael Gordon G, Taylor Hugh S, Zhang Xuchen, Li Da, Huang Yingqun
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America.
Center of Reproductive Medicine, National Health Commission Key Laboratory , Shengjing Hospital of China Medical University, Shenyang, China.
J Clin Invest. 2025 Aug 12. doi: 10.1172/JCI194879.
Through a combination of single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by TET3 overexpression (Toe-Macs) in three major human diseases associated with chronic inflammation: metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enables their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 knockout markedly mitigates disease progression and the therapeutic effects are recapitulated pharmacologically using a TET3-specific small molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulates expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.
通过结合单细胞/单细胞核RNA测序（sc/snRNA-seq）数据分析、免疫组织化学和原代巨噬细胞研究，我们在与慢性炎症相关的三种主要人类疾病中鉴定出了以TET3过表达为特征的致病性巨噬细胞（Toe-Macs）：代谢功能障碍相关脂肪性肝炎（MASH）、非小细胞肺癌（NSCLC）和子宫内膜异位症。这些巨噬细胞由疾病微环境（DME）中存在的共同因素诱导产生。至关重要的是，这些巨噬细胞普遍依赖TET3过表达，这使得它们能够作为一个单一群体被选择性清除，而不考虑其他分子标记的异质性。在小鼠中，通过髓系特异性Tet3基因敲除来清除这些巨噬细胞，可显著减轻疾病进展，并且使用TET3特异性小分子降解剂在药理学上可重现治疗效果。通过一种意想不到的作用方式，TET3在表观遗传上调节多个对炎症/免疫抑制性DME的产生和维持至关重要的基因的表达。我们提出，Toe-Macs是致病性巨噬细胞的一个统一特征，可作为治疗靶点来治疗MASH、NSCLC、子宫内膜异位症以及可能的其他慢性炎症性疾病。
