Exosomal miR‑301a‑3p of airway epithelial cells regulates macrophage polarization and promotes lung injury via the GATA1 pathway in acute respiratory distress syndrome

Abstract

Abstract Objectives: Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality rates, and macrophage polarization is critical for its pathogenesis. Exosomes are crucial inflammation mediators; however, airway epithelial cell-derived exosome functions and their mechanisms remain unclear. Methods: We investigated effects of airway epithelial cell-derived exosomes on lipopolysaccharide (LPS)-induced ARDS in mice. Exosomes isolated from bronchial alveolar lavage fluid of phosphate-buffered saline or LPS-treated mice were injected to C57BL/6 wild type mice intratracheally; macrophage polarization, cytokine secretion, and cell apoptosis were examined. In an in vitro co-culture system, human macrophage precursor (THP-1) was co-cultured with these exosomes. Results: LPS-induced exosomes promoted M1 macrophage polarization, cytokine secretion, and apoptosis in vivo and in vitro co-culture models. Bioinformatic analysis indicated that miR-301a-3p-mediated LPS-Exosomes (LPS-Exo) functioned via targeting GATA1 downstream pathway in macrophages. Administering miR-301a-3p mimic significantly aggravated LPS-Exo-induced M1 macrophage polarization, inflammatory response, and lung injury, which was partially reversed by miR-301a-3p inhibitor. The miR-301a-3p mediated LPS-Exo function via upregulating the GATA1/NF‑κB and downregulating GATA1/Akt pathways in macrophages. Conclusions: Exosomal miR-301a-3p derived from airway epithelial cells aggravates ARDS development via inducing M1 macrophage polarization and promoting lung injury via activating the GATA1 pathway.