Macrophages Mediate Antiviral Immunity and Repair of Type 2 Alveolar Epithelial Cells in a Human Stem Cell Model

The lung alveoli are constantly exposed to inhaled pathogens and inorganic hazards, relying on robust defence mechanisms to maintain homeostasis. Alveolar macrophages and type 2 alveolar epithelial cells (AT2s) collaborate to orchestrate protection. Compromised defence can dysregulate immunity and repair, leading to acute and chronic respiratory diseases. To better understand these processes and drive therapeutic discovery, human model systems that capture key cell interactions are essential. Here, we develop the first induced pluripotent stem cell (iPSC)-derived platform that integrates AT2 cells and macrophages in an air-liquid interface culture. Coculture enhanced AT2-specific gene expression and lipid synthesis, while macrophages actively phagocytosed AT2-derived surfactant. iPSC-derived AT2s supported macrophage survival by producing M-CSF and coculture promoted an alveolar macrophage-like phenotype. Additionally, during respiratory infection macrophages played a crucial role in modulating proinflammatory signalling, enhancing antiviral immunity, and restricting viral replication. Furthermore, we identify a role for iPSC-derived macrophages in epithelial repair, with VEGF signalling to macrophages increasing epithelial permeability. We present an iPSC-derived air-interface platform to study AT2-macrophage interactions in homeostasis, infection, and repair, providing insights into their potential roles in the initiation and progression of respiratory diseases.