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Bitter and sweet taste receptors regulate human upper respiratory innate immunity
Robert J. Lee, … , Robert F. Margolskee, Noam A. Cohen
Robert J. Lee, … , Robert F. Margolskee, Noam A. Cohen
Published February 17, 2014
Citation Information: J Clin Invest. 2014;124(3):1393-1405. https://doi.org/10.1172/JCI72094.
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Research Article Pulmonology Article has an altmetric score of 236

Bitter and sweet taste receptors regulate human upper respiratory innate immunity

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Abstract

Bitter taste receptors (T2Rs) in the human airway detect harmful compounds, including secreted bacterial products. Here, using human primary sinonasal air-liquid interface cultures and tissue explants, we determined that activation of a subset of airway T2Rs expressed in nasal solitary chemosensory cells activates a calcium wave that propagates through gap junctions to the surrounding respiratory epithelial cells. The T2R-dependent calcium wave stimulated robust secretion of antimicrobial peptides into the mucus that was capable of killing a variety of respiratory pathogens. Furthermore, sweet taste receptor (T1R2/3) activation suppressed T2R-mediated antimicrobial peptide secretion, suggesting that T1R2/3-mediated inhibition of T2Rs prevents full antimicrobial peptide release during times of relative health. In contrast, during acute bacterial infection, T1R2/3 is likely deactivated in response to bacterial consumption of airway surface liquid glucose, alleviating T2R inhibition and resulting in antimicrobial peptide secretion. We found that patients with chronic rhinosinusitis have elevated glucose concentrations in their nasal secretions, and other reports have shown that patients with hyperglycemia likewise have elevated nasal glucose levels. These data suggest that increased glucose in respiratory secretions in pathologic states, such as chronic rhinosinusitis or hyperglycemia, promotes tonic activation of T1R2/3 and suppresses T2R-mediated innate defense. Furthermore, targeting T1R2/3-dependent suppression of T2Rs may have therapeutic potential for upper respiratory tract infections.

Authors

Robert J. Lee, Jennifer M. Kofonow, Philip L. Rosen, Adam P. Siebert, Bei Chen, Laurel Doghramji, Guoxiang Xiong, Nithin D. Adappa, James N. Palmer, David W. Kennedy, James L. Kreindler, Robert F. Margolskee, Noam A. Cohen

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Figure 1

Calcium responses in sinonasal ALIs during stimulation with denatonium benzoate.

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Calcium responses in sinonasal ALIs during stimulation with denatonium b...
(A) Representative trace showing dose-dependent calcium elevations in response to denatonium. 0.1 D, 0.1 mM denatonium benzoate; 1 D, 1 mM denatonium benzoate; 10 D, 10 mM denatonium benzoate. (B) Dose response plot of data from experiments shown in A. Each red data point is the mean of results from 5 to 12 experiments. (C) Representative images showing propagation of calcium signal from single denatonium-responding cells compared to global calcium mobilization by ATP. denat., denatonium. (D and E) Signal propagation was blocked in the presence of (D) 100 μM carbenoxolone (cbx), a gap junction inhibitor, (E) but not apical apyrase. Arrows denote single denatonium-responsive cells. Images shown are representative of 5 to 12 experiments for each condition. Scale bar: 50 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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