Allergen induces pulmonary neuroendocrine hyperplasia in asthma

Asthma is characterized by exacerbated responses to environmental triggers such as allergen. While pulmonary neuroendocrine cells (PNECs), a rare population of airway epithelial cells, are essential for amplifying allergen-induced asthma response, how they are regulated to achieve this role remains poorly understood. Here we show that in the adult mouse airway, inactivation of achaete-scute like 1 (Ascl1) gene in PNECs led to loss of these cells. Intriguingly, exposure of these mutants to house dust mites (HDM), a common allergen, led to reappearance of PNECs. Similarly, exposure of wild-type mice to HDM led to PNEC hyperplasia, a result of proliferation of existing PNECs and transdifferentiation from club cells. Single cell RNAseq experiments revealed PNEC heterogeneity, including the appearance of an allergen-induced PNEC subtype. Intracellular Notch1 is downregulated in HDM-treated airway, and treatment by Notch agonist prevented PNEC hyperplasia. These findings together suggest that HDM-induced PNEC hyperplasia may contribute to exacerbated asthma response. Overall design: Single cell RNA-seq from purified adult airway epithelial cells, enriched with Ascl1-lineaged cells, of saline and HDM-challenged lungs