Defining the role of Oncostatin M in lung homeostasis 2261154

Abstract Introduction As the primary site of gas exchange, the lung presents a large surface area that is continuously exposed to the external environment. To preserve lung function, cells within the alveolar niche must maintain homeostasis while defending against pathogens. Alveolar macrophages (AMs) and alveolar type II (ATII) epithelial cells collaborate through reciprocal signaling to preserve this delicate balance. Our previous work identified a novel role for macrophage-derived Oncostatin M (OSM) in restoring the epithelial barrier following viral-induced injury and revealed that OSM regulates epithelial transcriptional programs even at steady state. However, the mechanisms through which OSM maintains alveolar homeostasis are not yet fully defined. Methods We performed transcriptional profiling of ATII and AM populations isolated from wild-type and OSM-deficient mice at steady state, as well as following administration of exogenous OSM. Complementary analyses, including flow cytometry, immunofluorescence microscopy, ELISA, and cholesterol assays, were used to further characterize the alveolar niche. Results Loss of OSM altered the transcriptional states of both ATIIs and AMs. In ATIIs, genes regulating cholesterol homeostasis were downregulated, while lipid metabolism pathways were altered in AMs. Administration of exogenous OSM to the lung restored the transcriptional profiles of both cell types toward wild-type states. Conclusion These findings suggest that OSM helps maintain the steady-state alveolar niche by regulating cholesterol homeostasis through modulation of ATII cell states. Ongoing work will define how macrophages sense and respond to the alveolar environment to sustain epithelial homeostasis. Funding Source National Institute of Health (NIH) grant # R35GM150816 (RAF) and the Harvard FAS Dean’s Competitive Fund for Promising Scholarship (RAF). YLwas supported by NIH grant # TL1TR002543. Topic Categories Cytokines and Chemokines and their Receptors (CCR)