The miR-125a-5p/IRF4 Axis Mediates Sodium Arsenite-Induced M2 Macrophage Polarization

TL;DR

The study shows how arsenic exposure promotes M2 macrophage polarization through a specific microRNA and protein interaction, offering new insights into immune dysfunction and cancer.

Contribution

This study identifies a novel miR-125a-5p/IRF4 axis mediating arsenic-induced M2 macrophage polarization.

Findings

Sodium arsenite exposure increases M2 macrophage markers and decreases M1 markers in rat tissues and THP-1 macrophages.

miR-125a-5p overexpression reverses M2 polarization by inhibiting IRF4, reducing M2 markers and restoring M1 proteins.

Abstract

Arsenic, a ubiquitous metalloid, is commonly found in surface waters; as well as serious human health issues, it also induces systemic diseases and carcinogenesis upon chronic exposure. To better understand how arsenic potentially alters the immune system, it is important to study its effects on macrophage polarization. Micro-RNA plays an epigenetic regulatory role in organisms. The miR-125 family regulates macrophage polarization and tumorigenesis, yet its role in arsenic-induced macrophage polarization remains unexplored. This study investigated the mechanism of sodium arsenite (NaAsO2)-driven macrophage polarization via miR-125a-5p. In vivo, rats exposed to 10 or 50 mg/L NaAsO2 for 12 weeks exhibited elevated M2 markers (CD206, Arg1) and reduced M1 markers (iNOS, IL-1β, TNF-α) in liver and bladder tissues. In vitro, THP-1-derived macrophages treated with NaAsO2 (2–8 μM) for 48 h showed dose-dependent M2 polarization, marked by upregulated CD206, Arg1, and IL-10. Flow cytometry results show that the proportion of M2/M1-type cells has increased significantly. Notably, NaAsO2 suppressed miR-125a-5p expression and elevated interferon regulatory factor 4 (IRF4), a predicted target of miR-125a-5p. Overexpression of miR-125a-5p reversed NaAsO2-induced M2 polarization by inhibiting IRF4, thereby reducing M2 markers and restoring M1-associated proteins. These findings reveal that NaAsO2 promotes M2 macrophage polarization through the miR-125a-5p/IRF4 axis, highlighting a novel epigenetic mechanism in arsenic-associated tumor microenvironments and immune dysfunction. This study provides critical insights into targeting miR-125a-5p as a therapeutic strategy.

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