Single-cell atlas reveals alveolar macrophage-specific Oncostatin-M drives pulmonary fibrosis via fibroblast activation in PCV2d infection

Abstract A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix(1). Clarifying the cell-specific mechanisms by which viruses induce this process is crucial for developing effective strategies to intervene in disease progression. Here, we demonstrate that alveolar macrophage subsets specifically express tumor suppressor M (Osm) after infection by PCV2d infection and related intervention experiments in mice, combined with single-cell transcriptome sequencing (scRNA-seq). Through validation using histopathological analyses and an in vitro macrophage-fibroblast co-culture model, these alveolar macrophage-derived oncostatin M (Osm) were confirmed to specifically drive fibroblast activation. Vaccine intervention experiments further confirmed that targeted inhibition of oncostatin M (Osm) expression in alveolar macrophages significantly attenuated fibroblast activation and extracellular matrix deposition, thereby mitigating pulmonary fibrosis progression. Therefore, subgroup-specific secretion of oncostatin M (Osm) by alveolar macrophages represents a key driver mediating PCV2d infection-induced pulmonary fibrosis, and targeting this pathway offers a potential therapeutic strategy for viral-induced pulmonary fibrosis. - Abbreviations - Acronym - Full Name - Col1a2 - Encoding type I collagen - Timp3 - Matrix metalloproteinase inhibitor - IL1b - Interleukin-1B - Osm - Oncostatin M - PCV2d - The porcine circovirus type 2d - PF - Pulmonary fibrosis - ECM - Extracellular matrix - MPS - Mononuclear phagocytes - ECs - Endothelial cells - NK cells - TandNK cells - EP cells - Epithelial Cells - PAM - Macrophage - PLF - Fibroblast - DMEM - Dulbecco’s Modified Eagle Medium