Franklin, Ruth A.Rodríguez-Morales, Patricia Nichole2026-01-1320252025-06-052025Rodríguez-Morales, Patricia Nichole. 2025. Unveiling a novel role for macrophages in maintaining and restoring lung epithelial homeostasis. Doctoral Dissertation, Harvard University Graduate School of Arts and Sciences.32040783https://dash.harvard.edu/handle/1/42725054Due to its constant exposure to the external environment, the respiratory tract serves as a primary entryway for pathogens, including respiratory viruses. Infection causes lung injury through both direct viral infection of epithelial cells and collateral damage from antiviral immune responses. To preserve barrier integrity and maintain gas exchange, tissue repair mechanisms must function even during active antiviral immune responses. Macrophages, innate immune cells present in all tissues, are essential for homeostasis, host defense, and tissue repair. Given their strategic positioning and functional versatility, we hypothesized that lung macrophages, in the context of infection, provide signals to limit the detrimental effects of antiviral responses and promote epithelial repair in the damaged lung. Our work identified Oncostatin M (OSM) as a key cytokine with distinct roles in maintaining lung homeostasis and responding to viral challenges. Single-cell transcriptional profiling and genetic mouse models revealed lung macrophages as a major source of OSM. At baseline, Osm-deficient mice exhibited altered alveolar type II (ATII) epithelial cell states, a defect reversible with daily administration of OSM to the lung for one week. Following challenge with viral stimuli, Osm-deficient mice displayed elevated type I interferon (IFN-I) levels, more severe lung damage, and increased mortality, indicating that OSM is required for host survival. Notably, Osm deficiency resulted in a significant loss of ATII cells following challenge, a hallmark of alveolar injury. While IFN-I is crucial for antiviral defense, its dysregulation leads to exacerbated inflammation, cell death, tissue damage, and impaired repair. Upon challenge with viral stimuli, blockade of IFN-I signaling protected macrophage-specific Osm-deficient mice from morbidity and mortality. Moreover, OSM delivery to the lungs of these mice was sufficient to reduce morbidity and restore ATII cell numbers, even in the presence of elevated IFN-I levels. Consistent with these findings, in alveolar organoids, OSM treatment promoted organoid formation, counteracting IFN-I’s inhibitory effects on cell growth. Thus, OSM functions as a key growth factor that accelerates repair and preserves epithelial integrity alongside antiviral defenses. Altogether, these findings identify OSM as an essential macrophage-derived factor that maintains homeostasis of lung epithelial cells and promotes their proliferation to overcome IFN-I-mediated immunopathology.application/pdfenepithelial cellshomeostasislungmacrophagesrepairImmunologyThesis or Dissertation2026-01-130000-0002-2646-4482