Extracellular vesicles from alveolar macrophages promotes pulmonary fibrosis through suppression of lung alveolar regeneration

Pulmonary fibrosis (PF) is a type of progressive interstitial lung disease characterized by varying degrees of lung interstitial fibrosis. Lung alveolar regeneration failure in PF is critical for mediating this incurable disease. Here, we report that chronic lung injury induces the release of extracellular vesicles (EVs) from alveolar macrophages (AMs) to promote PF development by inhibiting alveolar regeneration. Mechanistically, the acetylation of mixed lineage kinase domain-like protein (MLKL), which is mediated by the upregulation of acetylase lysine acetyltransferase 5 (KAT5) following chronic lung injury, enhances its capacity to facilitate endosomal trafficking and the production of EVs from AMs. Those EVs, which are taken up by type 2 alveolar epithelial cells (AEC2s), release miR-148a-3p to repress the endogenous β-catenin agonist Wnt10b and exert an inhibitory effect on AEC2 renewal. Disruption of the KAT5-MLKL interaction or pharmacological inhibition of miR-148a-3p expression restores the regenerative capacity of AEC2s, with potent therapeutic efficacy in PF. Our study suggests a potential therapeutic option for PF.