Airway Goblet Metaplasia Resulting from YAP/TAZ Deletion Drives Pulmonary Inflammatory Responses

The increased presence of goblet epithelial cells in conducting airways of the respiratory system is common in pulmonary disorders and is often accompanied by disrupted immune and alveolar responses. Signaling effectors that restrict goblet cell production include YAP and TAZ, transcriptional regulators of Hippo signaling, which repress goblet cell differentiation in the airway epithelium. Here, we investigated the acute responses to goblet cell metaplasia that are induced by the conditional loss of YAP/TAZ in club epithelial cells of adult mouse lungs. We found that the increased production of goblet epithelial cells drives inflammatory states broadly throughout airway and alveolar epithelial cells, including in distal alveolar type II (AT2) epithelial cells. We demonstrate that goblet cells produce factors that rapidly activate alveolar macrophages, which stimulate AT2 inflammatory responses, and that depletion of alveolar macrophages rescues AT2 responses to aberrant goblet cell production. These findings demonstrate direct roles for goblet cells in triggering inflammatory signals and reveal a circuitry of cellular communication that is initiated by mucus-producing cells in the lung.