Type I interferon primes the alveolar epithelium to receive reparative signals from tissue-resident macrophages

Abstract Lung repair in response to viral infection requires integrated communication between epithelial and immune compartments, yet the impact of antiviral mediators on epithelial regenerative capacity remains poorly defined. Here, we demonstrate that type I interferon (IFN-I) signaling primes the lung for alveolar renewal following viral challenge. IFN-I contributes to the induction of an interferon-stimulated gene-high (ISG) hi Sca-1 Pos population of alveolar type II (ATII) epithelial cells. Sca-1 Pos ATIIs exhibit enhanced proliferative capacity and increased organoid-forming efficiency compared with their Sca-1 Neg counterparts. Viral challenge concurrently drives phenotypic reprogramming of tissueresident alveolar macrophages (trAMs). Sca-1 Pos ATIIs display heightened responsiveness to oncostatin M (OSM) and, following viral challenge, require trAM-derived OSM for their proliferation. Together, these findings reveal that viral stimuli induce coordinated IFN-I-dependent epithelial and macrophage states that poise the lung for regeneration, positioning IFN-I not only as a central antiviral defense mechanism but as a priming signal that prepares lung tissue for renewal.