microRNA expression profiles of extracellular vehicles released from alveolar macrophage

Interstitial lung diseases (ILDs) such as idiopathic pulmonary fibrosis (IPF) is diffuse parenchymal lung disorders characterized by varying degrees of inflammation and fibrosis of the lung interstitium. The failure of lung alveolar regeneration in IPF is critical for this incurable disease. Here we report that chronic lung injury causes a profibrotic phenotype of alveolar macrophages that release extracellular vehicles (EVs) to promote PF development through repressing the stemness traits of type 2 alveolar epithelial cells (AEC2s). We found that an increased expression of acetylases KAT5 interacts with and acetylates protein kinase MLKL, which directly promotes release of EVs from AMs following chronic lung injury. AEC2s takes up the EVs and releases miR-148a-3p to repress expression of endogenous b-catennin agonist Wnt10b and alveolar regeneration. Pharmacologic inhibition of the miR-148a-3p expression or interruption of the KAT5-MLKL interaction restores regenerative capacity of AEC2s and exhibits potent therapeutic efficacy against PF. Our study confers a potential strategy for the treatment of IPF and other interstitial lung diseases. miRNA profiles of extracellular vehicles secreted by alveolar macrophage from control and BLM-induced PF mice were generated by deep sequencing, in triplicate, using Illumina NextSeq 500.