Exosome miR‐6990‐5p from MMP14high Macrophage Promotes Fibrosis Through Th17 Cell Differentiation in Hypersensitivity Pneumonia

Th17 cells contribute to pulmonary fibrosis, but the mechanisms driving their differentiation remain unclear. Using single‐cell RNA sequencing (scRNA‐seq) and a decision tree model, we identify IL17A as a key marker in mice exposed to Saccharopolyspora rectivirgula antigen (SR‐Ag). Trajectory and T cell receptor (TCR) analyses reveal IL17A⁺ CD4 T cells as terminally differentiated and clonally expanded. Blocking IL17A reduces SR‐Ag–induced lung inflammation and fibrosis. Exosomal miR‐6990‐5p from MMP14‐overexpressing macrophages promotes Th17 differentiation and fibroblast‐to‐myofibroblast transition (FMT) in vitro. It directly targets STAT1, as confirmed by luciferase assays. Co‐immunoprecipitation (Co‐IP) and docking analyses show STAT1 interacts with ROR‐γt and RUNX1. STAT1 knockdown upregulates ROR‐γt, IL17A, and RUNX1 in co‐cultures with naïve CD4 T cells. In vivo, miR‐6990‐5p exacerbates fibrotic hypersensitivity pneumonitis (FHP) in SR‐Ag‐exposed mice. These findings indicate that miR‐6990‐5p induces Th17 cell differentiation through the STAT1/RUNX1/ROR‐γt/IL17A pathway, contributing to FMT and fibrosis progression. This highlights miR‐6990‐5p as a potential therapeutic target for FHP.