TET3-overexpressing macrophages are a unifying pathogenic feature with therapeutic potential in chronic inflammatory diseases
Shojiro Haji, Yoshihiro Ogawa
Shojiro Haji, Yoshihiro Ogawa
Published November 3, 2025
Citation Information: J Clin Invest. 2025;135(21):e198802. https://doi.org/10.1172/JCI198802.
View: Text | PDF
Commentary

TET3-overexpressing macrophages are a unifying pathogenic feature with therapeutic potential in chronic inflammatory diseases

Abstract

Increased activation of the NLRP3 inflammasome in immune cells, including macrophages, has been implicated in the pathogenesis of multiple chronic inflammatory diseases. Targeted depletion of macrophages has been explored as a cross-disease therapeutic strategy, but without subtype-specific markers, this strategy risks elimination of macrophages with homeostatic functions. In this study, Liu et al. identified a subpopulation of pathogenic macrophages, referred to as Toe-Macs, which are characterized by overexpression of the DNA demethylase TET3 in metabolic dysfunction–associated steatohepatitis (MASH), non–small cell lung cancer (NSCLC), and endometriosis. When induced into the disease microenvironment, Toe-Macs produced proinflammatory cytokines and chemokines. Selective elimination of Toe-Macs attenuated disease progression without any discernible side effects in mouse models of MASH and NSCLC. These findings highlight the role of Toe-Macs in the pathogenesis of chronic inflammatory diseases and provide a rationale for exploring TET3 as a therapeutic target.

Authors

Shojiro Haji, Yoshihiro Ogawa

×

Figure 1

Toe-Macs contribute to the pathogenesis of chronic inflammatory diseases.

Options: View larger image (or click on image) Download as PowerPoint
Toe-Macs contribute to the pathogenesis of chronic inflammatory diseases...
(A) Liu et al. reported that overexpression of TET3 in macrophages is induced by TGF-β1 and CCL2 derived from the DME of MASH, NSCLC, and endometriosis. TET3 is recruited to the promoter regions of NLRP3, IL1B, TGFB1, CCL2, and CD274 via interaction with phosphorylated STAT3 and induces an open chromatin conformation to upregulate the expression of NLRP3, IL-1β, TGF-β1, CCL2, and PD-L1 epigenetically, thereby leading to the exacerbation of these chronic inflammatory diseases. In addition, CCL2 and TGF-β1 released from Toe-Macs could increase TET3 expression through a positive feedback loop. (B) Bobcat339, a TET3-specific degrader, does not induce apoptosis in healthy macrophages but selectively trigger apoptosis in Toe-Macs. Therefore, selective elimination of Toe-Macs by using Bobcat339 could mitigate disease progression with reduced side effects.