Macrophage-derived oncostatin M repairs the lung epithelial barrier during inflammatory damage
Daisy A. Hoagland, Patricia Rodríguez-Morales, Alexander O. Mann, A Vazquez, Shuang Yu, Alicia Lai, Harry Kane, Susanna M. Dang, Yunkang Lin, Louison Thorens, Shahinoor Begum, M. Castro, Scott D. Pope, Jaechul Lim, Shun Li, Xian Zhang, Ming O. Li, Carla F. Kim, Ruaidhrí Jackson, Ruslan Medzhitov, Ruth A. Franklin
Abstract
Tissue repair programs must function alongside antiviral immunity to restore the lung epithelial barrier following infection. We found that macrophage-derived oncostatin M (OSM) counteracted the pathological effects of type I interferon (IFN-I) during infection and damage in mice. At baseline, OSM-deficient mice exhibited altered alveolar type II (ATII) epithelial cell states. In response to influenza or viral mimic challenge, mice lacking OSM exhibited heightened IFN-I responses and increased mortality. OSM delivery to the lung induced ATII proliferation and was sufficient to protect deficient mice against morbidity. Furthermore, OSM promoted organoid formation despite the growth-inhibitory effects of IFN-I. These findings identify OSM as an indispensable macrophage-derived growth factor that maintains the homeostasis of lung epithelial cells and promotes their proliferation to overcome IFN-I-mediated immunopathology.