Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection
Monika I. Hollenhorst, … , Ulrich Boehm, Gabriela Krasteva-Christ
Monika I. Hollenhorst, … , Ulrich Boehm, Gabriela Krasteva-Christ
Published May 3, 2022
Citation Information: J Clin Invest. 2022;132(13):e150951. https://doi.org/10.1172/JCI150951.
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Research Article Immunology Pulmonology

Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection

Abstract

Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into first-line defense mechanisms against bacterial infections of the lung.

Authors

Monika I. Hollenhorst, Rajender Nandigama, Saskia B. Evers, Igor Gamayun, Noran Abdel Wadood, Alaa Salah, Mario Pieper, Amanda Wyatt, Alexey Stukalov, Anna Gebhardt, Wiebke Nadolni, Wera Burow, Christian Herr, Christoph Beisswenger, Soumya Kusumakshi, Fabien Ectors, Tatjana I. Kichko, Lisa Hübner, Peter Reeh, Antje Munder, Sandra-Maria Wienhold, Martin Witzenrath, Robert Bals, Veit Flockerzi, Thomas Gudermann, Markus Bischoff, Peter Lipp, Susanna Zierler, Vladimir Chubanov, Andreas Pichlmair, Peter König, Ulrich Boehm, Gabriela Krasteva-Christ

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Figure 4

The denatonium-induced neurogenic inflammation is mediated via cholinergic signaling and sensory nerve activation.

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The denatonium-induced neurogenic inflammation is mediated via cholinerg...
(A) Nerve fibers (PGP9.5+: red) containing the neuropeptide CGRP (yellow) in Chat-eGFP mice (ChAT+ cells: green, stars). Arrowheads: neuroendocrine cells labelled for PGP9.5 and/or CGRP. Scale bar: 50 μm. (B) Quantification of Evans blue (EB) extravasation in response to 1, 10, or 20 mM denatonium in WT mice treated with the AChR antagonists mecamylamine (MEC) and atropine. (C) Analysis of neutrophil numbers per tracheal ring in WT mice treated with MEC and atropine. (D) Quantification of EB extravasation in response to 1, 10, or 20 mM denatonium in Trpa1-DTR mice treated with diphtheria toxin (DT) and in response to 1 mM denatonium in naive WT or DT-treated WT (Trpa1+/+) mice. (E) Analysis of neutrophil number per tracheal ring in response to 1, 10, or 20 mM denatonium in Trpa1-DTR mice treated with DT. Naive or DT-treated WT (Trpa1+/+) mice stimulated with 1 mM denatonium served as controls. (F) Staining of venules (arrows) and capillaries (stars) in tracheae from DT-treated Trpa1-DTR mice. BC: Trpm5 (red), blood vessels: CD31 (yellow), nerves: CGRP (yellow, arrowheads). Scale bar: 50 μm. (G and H) Quantification of the venule (G) and capillary diameter (H). n = 29–41 vessels from 4 mice. In B–E, G, and H, data are shown as single values and mean ± SEM (n = 14–24 rings from 3–4 mice). *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA followed by Bonferroni’s multiple-comparison correction (B–E) or 2-tailed, unpaired Student’s t test (G and H).