C32-28 Vagal Sensory Neurons Regulate Coordinated Airway Immune and Epithelial Polarization

Abstract

The airway mucosa directly interfaces with the airstream, serving as both a sensor of inhaled threats and a coordinator of protective responses through distinct but highly integrated cellular compartments. In addition to well established sentinel populations of airway epithelial and resident immune cells, the airways are densely innervated by afferent sensory fibers predominantly originating from the vagal ganglion, which participate in regulating respiratory immune responses and reflexes that protect the lung from a range of threats. Vagal sensory neurons have been implicated in both allergic type 2 and antibacterial type 17 inflammation as well as in regulating epithelial mucus secretion. However, its role in coordinating integrated tissue responses and in diseases with mixed inflammatory endotypes remains unclear. To address this question, we performed single-cell RNA sequencing of airways following house dust mite (HDM)-induced inflammation with conditional ablation of vagal sensory neurons. Surprisingly, we found that systemic ablation of sensory neurons drives profound changes across cellular compartments. Allergen-induced goblet cell metaplasia was strongly reduced, with the airway epithelium polarized towards bacterial defense, highlighted by the emergence of a novel club cell state distinguished by a battery of anti-microbial gene expression. In parallel, infiltration of classic type 2 inflammatory cell, including eosinophil and Th2 cells, was shifted towards pronounced neutrophilia and increased gamma-delta T cells. We demonstrate that this coordinated epithelial and immune polarization is independent of nociceptive neurons, using both chemotoxic and genetic ablation approaches. Direct vagal ganglia-specific neuronal ablation prior to HDM administration confirmed the role of vagal sensory neurons. In aggregate, we demonstrate that vagal sensory neurons mediate coherent organ-wide epithelial and immune responses targeted towards distinct types of threats.

This abstract is funded by: None