# Neural Circuits between Nodose Ganglion and Pulmonary Neuroendocrine Cells Regulate Lung Inflammatory Responses

## TL;DR

The study reveals a neural circuit in the lungs that detects harmful substances and amplifies inflammation through interactions between nerve cells and specialized lung cells.

## Contribution

The discovery of a feed-forward neural-epithelial circuit involving TRPA1+αCGRP+ sensory neurons and PNECs in regulating lung inflammation.

## Key findings

- Vagal sensory endings synapse with PNECs and detect bacterial endotoxins via TRPA1.
- TRPA1 detection triggers αCGRP production in nodose ganglia, which stimulates PNEC activation and proliferation.
- This neural circuit amplifies endotoxin-induced lung inflammation through a feed-forward loop.

## 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.

TRPA1+αCGRP+ sensory neurons in the nodose ganglion detect external insults such as lipopolysaccharide (LPS) and interact directly with pulmonary neuroendocrine cells (PNECs), promoting their activation and proliferation. This neural‐epithelial interaction amplifies lung inflammation. Our study uncovers a vagal sensory neuron‐PNEC neuroimmune circuit that plays a critical role in regulating pulmonary inflammatory responses.