Disruption of the Vagal TRPA1 ‐Pulmonary Neuroendocrine Cell Axis Reduces Asthma Severity

BACKGROUND: Pulmonary neuroendocrine cells (PNECs) are adjacent to the vagus nerve, which innervates the lungs, and have been implicated in asthma pathogenesis. However, the neuroimmunomodulatory role of vagal-PNEC signaling in asthma remains poorly understood. METHODS: We developed an asthma model of C-fiber photoactivation and vagotomy to investigate the changes in PNECs. RNA sequencing (RNA-seq) was performed on flow cytometry-sorted PNECs to explore how vagus nerve C fibers affect the function of PNECs, with further validation in an in vitro cell model. Single-nucleus RNA sequencing (snRNA-seq) was conducted on airway samples of patients before and after bronchial thermoplasty (BT) treatment, and the changes of neural signals in different airway cell types and their crosstalk with PNEC after BT were analyzed in depth. RESULTS: Vagotomy reduced photoactivated TRPA1-mediated PNEC activation and allergic inflammation, inhibited the number and function of PNEC, and attenuated PNEC-mediated asthma response. PNEC RNA-seq results showed that photoactivation of TRPA1 in lung could promote the migration, aggregation, and synaptic transmission of PNECs and increase the synthesis and secretion of neuropeptides, which could also be activated by α7 nAChR of PNECs. BT therapy significantly reduced or interrupted NRG1-ERBB signaling between PNECs and other cells by interfering with PNEC secretion, synapse formation, and signaling, thereby alleviating the condition of asthma patients. CONCLUSIONS: We found that the vagal TRPA1-PNEC axis contributes to asthma severity. BT can disrupt this pathway through NRG1-ERBB signaling between PNECs and other cells to attenuate the inflammatory response in asthma.