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

Baez Vazquez, A. Y.; Hoagland, D. A.; Mann, A. O.; Lin, Y.; Dang, S. M.; Hauptschein, M.; Thorens, L.; Begum, S.; Castro, M. A.; Rodriguez-Morales, P.; Lai, A.; Barrera, I.; Sun, D.; Shehaj, A.; Chen, F.; Benoist, C.; Kim, C. F.; Franklin, R. A.

doi:10.64898/2026.06.10.731366

bioRxiv · 10.64898/2026.06.10.731366

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

Baez Vazquez, A. Y.·Hoagland, D. A.·Mann, A. O.·Lin, Y.·Dang, S. M.·Hauptschein, M.·Thorens, L.·Begum, S.·Castro, M. A.·Rodriguez-Morales, P.·Lai, A.·Barrera, I.·Sun, D.·Shehaj, A.·Chen, F.·Benoist, C.·Kim, C. F.·Franklin, R. A.

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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-1Pos population of alveolar type II (ATII) epithelial cells. Sca-1Pos ATIIs exhibit enhanced proliferative capacity and increased organoid-forming efficiency compared with their Sca-1Neg counterparts. Viral challenge concurrently drives phenotypic reprogramming of tissueresident alveolar macrophages (trAMs). Sca-1Pos 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.

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Baez Vazquez, A. Y., Hoagland, D. A., Mann, A. O., Lin, Y., Dang, S. M., Hauptschein, M., Thorens, L., Begum, S., Castro, M. A., Rodriguez-Morales, P., Lai, A., Barrera, I., Sun, D., Shehaj, A., Chen, F., Benoist, C., Kim, C. F., Franklin, R. A.. 2026-06-12. Type I interferon primes the alveolar epithelium to receive reparative signals from tissue-resident macrophages. https://doi.org/10.64898/2026.06.10.731366

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