TET3 is a common epigenetic immunomodulator of pathogenic macrophages
Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang
Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang
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Research Article Hepatology Immunology Inflammation

TET3 is a common epigenetic immunomodulator of pathogenic macrophages

Abstract

Through a combination of single-cell/single-nucleus RNA-Seq (sc/snRNA-Seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by Tet methylcytosine dioxygenase 3 (TET3) overexpression (Toe-Macs) in 3 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 enabled their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 KO markedly mitigated disease progression, and the therapeutic effects were recapitulated pharmacologically using a TET3-specific small-molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulated the 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.

Authors

Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang

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Figure 8

Proposed model.

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Proposed model. TET3 overexpression is induced by CCL2 and TGF-β1, which...
TET3 overexpression is induced by CCL2 and TGF-β1, which are commonly present in the DME. TET3 downregulates let-7 expression, leading to increased production of IL-6. TET3 is recruited to specific gene promoters through interaction with activated STAT3. By binding to the promoters of NLRP3, IL1B, TGFB1, and CD274, TET3 induces 5hmC DNA modification and demethylation and creates an open chromatin state facilitating transcription. In the case of CCL2, a mechanism independent of DNA modification is involved. This results in an increase in protein production of NLRP3, pro–IL-1β, TGF-β1, CCL2, and PD-L1, as well as enhanced NLRP3 inflammasome activity, which in turn promotes the maturation and release of IL-1β. Furthermore, TGF-β1 and CCL2 released from the Toe-Macs can act as autocrine factors to increase TET3 expression, creating a positive feedback loop with TET3.