Interferon signaling primes the lung epithelium for macrophage-mediated repair 2261178

Abstract Introduction The lung is continuously exposed to the external environment and is therefore highly susceptible to infection and injury. Successful recovery following pathogen encounter requires coordinated responses between epithelial and immune compartments to restore homeostasis. Alveolar type II epithelial cells (ATIIs) act as progenitors for the alveolar epithelium, while alveolar macrophages (AMs) regulate inflammation and repair. Type I interferon (IFN-I), produced in response to viral stimuli, is essential for antiviral defense but has been traditionally viewed as antagonistic to tissue regeneration. However, whether early IFN-I sensing influences epithelial repair programs remains unclear. Methods We used in vivo models of infection (influenza) and viral stimuli (poly(I:C)) to investigate how IFN signaling influences ATII behavior. Transcriptional profiling, flow cytometry, immunofluorescence microscopy, lineage tracing, and ex vivo alveolar organoids were employed to assess ATII proliferation, phenotype, and interactions with macrophages. Results Acute IFN-I signaling in the lung transiently induced a Sca-1+ ATII population that constituted the primary proliferative subset in vivo. IFN-I exposure heightened ATII sensitivity to macrophage-derived growth factors, enhancing their responsiveness to reparative cues. Ex vivo, Sca-1+ ATIIs displayed increased organoid-forming efficiency compared with Sca-1⁻ ATIIs, consistent with elevated progenitor potential and regenerative capacity. Conclusion Together, these findings suggest that IFN-I sensing primes ATIIs for subsequent repair. This work uncovers a previously unrecognized role for IFN-I in preparing the lung epithelium for regeneration following inflammation and injury. Funding Source NIH R35GM150816, NIH F31HL172650 Topic Categories Mucosal and Regional Immunology (MUC)