Abstract

The lungs interface directly with the external environment, exposing them to airborne pathogens like endotoxins. We investigated whether the vagus nerve, which innervates the lungs-detects such pathogens. Using transcriptomics, tissue clearance imaging, electrophysiology, and cell-specific knockout models, we discovered that vagal sensory endings synapse with pulmonary neuroendocrine cells (PNECs). These nerve endings detect bacterial endotoxins primarily through the pain receptor TRPA1, not via Toll-like receptor 4 (TLR4). This detection triggers electrical excitation in vagal neurons and upregulates neuropeptide (e.g., αCGRP) production in the nodose ganglia. Released αCGRP then acts back on PNECs, stimulating their neuropeptide synthesis and proliferation. This creates a feed-forward loop that amplifies endotoxin-induced lung inflammation. Our findings reveal a critical neural circuit between the nodose ganglion and PNECs that regulates pulmonary inflammatory responses.