Brush cells fine-tune neurogenic inflammation in the airways

Abstract

Airway epithelial cells, once considered a simple barrier layer, are now recognized as providing an active site for antigen sensing and immune response initiation. Most mucosal sites contain chemosensory epithelial cells, rare and specialized cells gaining recognition for their unique functions in sensing and directing the immune response symphony. In this issue of the JCI, Hollenhorst, Nandigama, et al. demonstrated that tracheal chemosensory brush cells detected bitter-tasting substances, including quorum-sensing molecules (QSMs) generated by pathogenic Pseudomonas aeruginosa. The authors used various techniques, including genetic deletion of brush cells, genetic manipulation of brush cell signaling, deletion of sensory neurons, in vivo imaging, and infection models with P. aeruginosa, to show that QSMs increased vascular permeability and innate immune cell influx into the trachea. These findings link the recognition of bacterial QSMs to the innate immune response in the airways, with translational implications for airway inflammation and infectious pathology.

Figure 1. Brush cell–activating receptors direct protective and pathologic responses in the airways.

(i) Pseudomonas aeruginosa colonies communicate with QSMs to increase population growth and virulence. QSMs are detected by bitter-taste TAS2 receptors (TAS2Rs)on brush cells, leading to generation of acetylcholine (Ach), activation of sensory neurons, and release of neuropeptides, predominantly substance P. Substance P induces vascular permeability and neutrophil extravasation and in some instances is associated with mast cell degranulation. (ii) When P. aeruginosa population size reaches critical numbers, the bacteria directly activate sensory neurons for CGRP release, which is associated with the suppression of neutrophil function and inflammatory response. (iii) Brush cell activation through the SUCNR1 or P2Y2 receptors (P2Y2Rs) elicits the generation and release of IL-25 and cysteinyl leukotrienes, two proinflammatory mediators that synergize to drive a polarized mucosal type 2 immune response. LTC4, leukotriene C4; CysLT1R, cysteinyl leukotriene receptor 1; ILC2, type 2 innate lymphoid cell.