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.
View: Text | PDF
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

×

Figure 5

CGRP and SP trigger tracheal neurogenic inflammation in response to denatonium.

Options: View larger image (or click on image) Download as PowerPoint
CGRP and SP trigger tracheal neurogenic inflammation in response to dena...
(A and B) CGRP and SP measurements in excised tracheae with and without denatonium stimulation in WT (Trpm5+/+) and Trpm5–/– mice (n = 5–7 samples from 6–10 mice). (C and D) Staining of CGRP+ (C) and SP+ (D) nerve fibers (arrowheads) in tracheal slices of control (vehicle) and denatonium-treated WT mice. L, lumen; E, epithelium; LP, lamina propria. Scale bars: 50 μm (C and D). (E and F) Quantification of contacts between BCs and CGRP+ (E) and SP+ (F) nerve endings in whole-mount preparations of tracheae treated with vehicle or 1 mM denatonium (n = 15–29 image stacks containing 16–77 contacts/sample from 8 mice). (G and H) Treatment of tracheae with 1 mM denatonium significantly reduced the CGRP+ (G) and the SP+ (H) nerve fiber volume (normalized to the total stack volume) in Trpm5+/+ but not in Trpm5–/– mice (n = 12–23 volumes from 4 mice). (I) 3D reconstruction of a whole-mount tracheal preparation immunofluorescence with Imaris software (see Supplemental Methods). BCs (GFP, green) are approached by CGRP+ nerves. (J) Nerve endings approaching BCs are CGRP+ and SP+. Scale bars: 20 μm (left images in I and J) and 10 μm (right images). In A, B, and E–H, data are shown as single values ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA followed by Bonferroni’s multiple-comparison correction (A and B) or 2-tailed, unpaired Student’s t test (E–H).