Fig. 8.

Schematics of the clarified COPD pathological model derived from our human COPD lung single-cell atlas. Monocytes orchestrate the “COPD core” pathogenesis, which starts from pro-inflammatory factors synthesized and secreted by monocytes, transmits via CCIs, and eventually leads to inflammatory injury of alveolar epithelia. In aged lungs, the IFN/MHC I axis-induced autoimmune airway epithelial niche modulated by stemness-exhausted aged club cells may be potentiated by monocytes via IFN-γ stimulator IL18 and could facilitate COPD development via cytotoxic damage of airway epithelia. Under smoking conditions, enhanced intercellular communications between macrophages and endothelial cells depending on both ligands–receptors interactions and bioactivated sphingolipids metabolites impair pulmonary endothelial barriers, which could exacerbate inflammatory destruction of alveolar epithelia with a concomitant increased capacity for antigen presentation via MHC class II of innate immune cells including monocytes, DCs, macrophages, and neutrophils