Exosomal miRNA reprogramming in pyroptotic macrophage drives silica-induced fibroblast-to-myofibroblast transition...

Silicosis is an occupational lung disease characterized by progressive pulmonary fibrosis, threatening millions of occupational workers worldwide due to a lack of effective treatments. To unveil mechanisms underlying silica-induced pulmonary fibrosis, we established in vitro and in vivo silicosis models, then employed scRNA-sequencing to profile the cellular landscape of lung tissues followed by characterization of macrophage pyroptosis and exosome therefrom in driving fibroblast-to-myofibroblast-transdifferentiation. Using hyperspectral imaging and artificial intelligence-powered pathological recognition, we found that silica nanoparticle (SiNP) triggered progressive lung fibrosis in vivo, and scRNA-seq implicated interstitial macrophage as pivotal regulators for fibroblast transdifferentiation. Mechanistically, SiNPs were demonstrated to induce macrophage pyroptosis and liberate exosomes, which upregulated pro-fibrotic markers and promoted myofibroblast transition. Subsequent high-throughput miR-sequencing revealed distinct exosomal miRNA signatures that modulated TGF-β signaling and induced fibroblast transdifferentiation. Lastly, we administered these exosomes into silicotic mice and found exacerbated inflammatory infiltration and pulmonary fibrosis. In conclusion, SiNPs exposure caused the remodeling of exosomal miRNAs by inducing interstitial macrophage pyroptosis, and exosomes derived from pyroptotic macrophage fuel fibroblast transdifferentiation by creating a pro-fibrotic microenvironment and promoting silicotic fibrosis. These findings provide critical insights into the pathogenesis of silicosis and the formulation of emerging therapeutic strategies.