Specific upregulation of extracellular miR-6238 in particulate matter-induced acute lung injury and its immunomodulation

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases characterized by a severe inflammatory response and the destruction of alveolar epithelium and endothelium. ALI/ARDS is caused by pathogens and toxic environmental stimuli, such as particulate matter (PM). However, the general symptoms of ALI/ARDS are similar, and determining the cause of lung injury is often challenging. In this study, we investigated whether there is a critical miRNA that characterizes PM-induced ALI. We found that the expression of miR-6238 is specifically upregulated in lung tissue and lung-derived extracellular vesicles (EVs) in response to PM exposure. Notably, bacterial endotoxin (Lipopolysaccharide; LPS or peptidoglycan; PTG) does not induce the expression of miR-6238 in the lung. Instead, the expression of miR-155 is dramatically increased in LPS-induced ALI. We further demonstrated that human lung epithelial cells and macrophages predominantly produce miR-6238 and miR-155, respectively. Mechanistically, EV-miR-6238 is effectively internalized into alveolar macrophages (AMs) and regulates inflammatory responses in vivo. CXCL3 is a main target of miR-6238 in AMs and modulates neutrophil infiltration into the lung alveoli. Collectively, our findings suggest that miR-6238 is a novel regulator of pulmonary inflammation and a putative biomarker that distinguishes PM-induced ALI from endotoxin (LPS/PTG)-mediated ALI. [Display omitted] •PM (non-infectious stimuli) and LPS (infectious stimuli) induce acute lung injury (ALI).•Lung-derived miR-6238 and miR-155–5p are specifically upregulated in PM- and LPS-induced ALI, respectively.•Both PM10 and PM2.5 can trigger the production of miR-6238 in lung.•Lung epithelial cells and macrophages robustly produce miR-6238 and miR-155–5p, respectively.•EV-miR-6238 regulates inflammatory macrophages during PM-induced ALI.