Airway goblet cells resulting from conditional YAP/TAZ deletion promote distinct pulmonary inflammation

Abstract The aberrant presence of goblet cells, which are epithelial cells of the conducting airways that have specialized roles in secreting mucus, is frequently associated with distinct innate and adaptive immune changes that together are hallmarks of various pulmonary diseases. The transcriptional regulators YAP and TAZ, key effectors of Hippo pathway signaling, play a central role in suppressing the differentiation of airway goblet cells. Here we investigated the consequences of goblet cell production, resulting from the YAP/TAZ conditional depletion in Scgb1a1+ secretory cells, on lung immunity. We observed that loss of YAP/TAZ resulted in the production of goblet cells promoting local CD45+ immune cell expansion. To gain insight into immune changes associated with the production of YAP/TAZ-deleted goblet cells, we performed a single-cell RNA sequencing experiment on CD45+ cells isolated from control and Yap/Taz-cNull mouse lungs. Data analyses, along with follow-up validation experiments, demonstrated significant immune changes in Yap/Taz-cNull mice including an expansion of type 2 innate lymphoid cells (ILC2s), CD4+ T cells Th2 polarization, and alternative activation of alveolar macrophages, accompanied with elevated type 2 cytokine production. Gene expression analysis of YAP/TAZ-deleted airway cells revealed altered expression of notable immune-modulating factors, many of which are implicated in lung diseases. Collectively our study demonstrates that key immune-modulating signals arise from the secretory lung epithelium through reduced YAP/TAZ activity, raising interesting questions about the functions of YAP/TAZ in lung homeostasis and about the contributions of goblet cells to shaping lung immune responses.