Fine Particulate Matter Induces Childhood Asthma Attacks via Extracellular Vesicle-Packaged Let-7i-5p-Mediated Modulation of the MAPK Signaling Pathway

Fine particulate matter less than 2.5 µm in diameter (PM 2.5 ) is a major risk factor for acute asthma attacks in children. However, the biological mechanism underlying this association remains unclear. In the present study, PM 2.5 -treated HBE cells-secreted extracellular vesicles (PM 2.5 -EVs) caused cytotoxicity in “horizontal” HBE cells and increased the contractility of “longitudinal” sensitive human bronchial smooth muscle cells (HBSMCs). RNA sequencing showed that let-7i-5p is significantly overexpressed in PM 2.5 -EVs and asthmatic plasma; additionally, its level is correlated with PM 2.5 exposure in children with asthma. The combination of EV-packaged let-7i-5p and the traditional clinical biomarker IgE exhibits the best diagnostic performance (area under the curve [AUC] = 0.855, 95% CI = 0.786–0.923). Mechanistically, let-7i-5p is packaged into PM 2.5 -EVs by interacting with ELAVL1 and internalized by both “horizontal” recipient HBE cells and “longitudinal” recipient-sensitive HBSMCs, with subsequent activation of the MAPK signaling pathway via suppression of its target DUSP1 . Furthermore, an injection of EV-packaged let-7i-5p into PM 2.5 -treated juvenile mice aggravated asthma symptoms. This comprehensive study deciphered the remodeling of the extracellular environment mediated by the secretion of let-7i-5p-enriched EVs during PM 2.5 -induced asthma attacks and identified plasma EV-packaged let-7i-5p as a novel predictor of childhood asthma.