Airway injury induces alveolar epithelial and mesenchymal responses mediated by macrophages

Summary Acute injury in the airways or the lung activates local progenitors and stimulates changes in cell-cell interactions to restore homeostasis, but it is not appreciated how more distant niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar, immune, and mesenchymal responses. Single-cell transcriptomics and in vivo validation revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific ablation. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) via upregulation of Spp1 which encodes the secreted factor Osteopontin. A previously uncharacterized mesenchymal population we termed Mesenchymal Airway/Adventitial Niche Cell 2 (MANC2) also exhibited dynamic changes in abundance and a pro-fibrotic transcriptional signature after club cell ablation in an AM-dependent manner. Overall, these results demonstrate that acute airway damage can trigger distal lung responses including altered cell-cell interactions that may contribute to potential vulnerabilities for further dysregulation and disease. Highlights - Airway epithelial cell injury causes proliferation of AT2 cells, the alveolar epithelial progenitor cells - Alveolar macrophages promote AT2 cell proliferation after airway injury via upregulation of Spp1 - Alveolar macrophages have a pro-fibrotic effect on lung mesenchyme after airway injury - Damage to one epithelial compartment can elicit altered epithelial- immune-mesenchymal cell crosstalk in another compartment of the same tissue