Macrophage-derived oncostatin M repairs the lung epithelial barrier during inflammatory damage

Tissue repair programs must function alongside antiviral immunity to restore the lung epithelial barrier following infection. We found that macrophage-derived oncostatin M (OSM) counteracted the pathological effects of type I interferon (IFN- I) during infection and damage in mice. At baseline, OSM-deficient mice exhibited altered alveolar type II (ATII) epithelial cell states. In response to influenza or viral mimic challenge, mice lacking OSM exhibited heightened IFN-I responses and increased mortality. OSM delivery to the lung induced ATII proliferation and was sufficient to protect deficient mice against morbidity. Furthermore, OSM promoted organoid formation despite the growth- inhibitory effects of IFN- I. These findings identify OSM as an indispensable macrophage-derived growth factor that maintains the homeostasis of lung epithelial cells and promotes their proliferation to overcome IFN-I–mediated immunopathology. Overall design: 8-12 week old Osm+/+ and Osm-/- female mice were intranasally with PBS or 225pfu of Influenza A Virus (A/WSN/33; H1N1). Lungs were harvested two days post-infection and digested with Dispase/Liberase/DNase mixture. A portion of the whole lung single cell suspension was stained with TotalSeq-B0301 (Biolegend, Catalog #155831) and TotalSeq-B0302 (Biolegend, Catalog #155833) for hash-tagging before encapsulation.