A vagal reflex evoked by airway closure

Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and on a moment-by-moment basis, enact vital reflexes to maintain respiratory function. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax, or airway compression. Here, we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses, and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, while ablating NEBs or vagal PVALB neurons eliminated gasping to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of PIEZO2 in NEBs also eliminated responses to airway closure. NEBs are dispensable for the Hering-Breuer inspiratory reflex, indicating that discrete terminal structures detect airway closure and inflation. Like Merkel cells involved in touch sensation, NEBs are PIEZO2-expressing epithelial cells, and moreover, are critical for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways, and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function. Lung neuroendocrine cells, which comprise neuroepithelial bodies (NEBs), were isolated from Ascl1-CreER; Ai14 and Calca-Egfp mice. Reporter expressing cells were enriched by fluorescence-activated cell sorting (FACS) and analyzed using scRNAseq.