Trichloroethylene induced hepatic injury via M1 macrophage polarization through KDM4A associated with the Wnt/β-catenin pathway in vitro and in vivo

Abstract

Background & Aims: Trichloroethylene (TCE) is a commonly used organic solvent in industry. Our previous studies have found that TCE can cause liver injury accompanied by macrophage polarization, but the specific mechanism is unclear. The epigenetic regulation of macrophage polarization is mainly focused on histone modification. Histone lysine demethylase 4A (KDM4A) is involved in the activation of macrophages. In this study, we used a mouse model we investigated the role of KDM4A in the liversof TCE-drinking mice and found that the expression of KDM4A, M1-type polarization indicators, and related inflammatory factors in the livers of TCE-drinking mice. Methods: In the study, BALB/c mice were treated with TCE by drinking water. The mice were randomly divided into 4 groups: 2.5 milligrams per milliliter (mg/mL) TCE dose group (n=24) and 5.0 mg/mL TCE dose group (n=24), TCE used 1% DMSO to aid solubilization, the vehicle control group (drinking water containing 1% DMSO) (n=24), and the blank control group (fed with normal drinking water) (n=24). Drinking water was replaced every 24 h to ensure the stability of the TCE concentration. The mice were sacrificed at four time points of 2, 4, 8 and 12 weeks, and biological sample material were taken aseptically. Results: TCE triggered M1 polarization of mouse macrophages, characterized by the expression of CD11c and robust production of inflammatory cytokines (e.g., TNF-α andIL-1β). Notably, exposure to TCE resulted in markedly increased expression of KDM4A in macrophages. Functionally, the increased expression of KDM4A significantly impaired the expression of H3K9me3 and H3K9me2 andincreased the expression of H3K9me1. In addition, KDM4A potentially represents a novel epigenetic modulator, with its upregulation connected to β-catenin activation, a signal critical for the proinflammatoryactivation of macrophages. Furthermore, KDM4A inhibitor JIB-04 treatment resulted in a decrease in β-catenin expression andprevented TCE-induced M1 polarization and the expression of the proinflammatory cytokines TNF-α and IL-1β. These results suggest that the association of KDM4A and Wnt/β-catenin cooperatively establishes the activation and polarization of macrophages and global changes in H3K9me3/me2/me1. Conclusion: Our findings identify KDM4A as an essential regulator of the polarization of macrophages and the expression of inflammatory cytokines, which might serve as a potential target for preventing and treating liver injury caused by TCE.