miR-124-3p derived from plasma exosomes enhances M2 macrophage polarization to treat acute lung injury

Abstract Acute lung injury (ALI) post–lung transplantation (LT) is a major clinical challenge. This study investigates the role of exosomal miR-124-3p in modulating macrophage polarization and ameliorating ALI. Using male C57BL/6J mice, we established a left lung orthotopic transplantation model. Transcriptomic analysis revealed that miR-124-3p was significantly downregulated in the plasma exosomes of LT mice. Functional experiments demonstrated that plasma exosomal miR-124-3p promotes M2 macrophage polarization by targeting Krüppel-like factor 6 (KLF6) and inhibiting the NF-κB pathway. Overexpression of miR-124-3p significantly reduced inflammation, enhanced lung tissue repair, and improved oxygenation indices in vivo. In vitro, exosomal miR-124-3p reduced M1 markers (iNOS, IL-1β, IL-6) and increased M2 markers (Arg1, Ym1, Fizz1) in macrophages, confirmed by flow cytometry and Western blot. Furthermore, overexpression of KLF6 reversed the therapeutic effects of miR-124-3p. This study identifies miR-124-3p as a critical regulator of macrophage polarization and ALI pathophysiology, providing a potential therapeutic target for managing ALI in lung transplant recipients.