Bitter and sweet taste receptors regulate human upper respiratory innate immunity
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
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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Research Article Pulmonology

Bitter and sweet taste receptors regulate human upper respiratory innate immunity

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 6

T2R agonists stimulate secretion of β-defensins from HSECs.

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T2R agonists stimulate secretion of β-defensins from HSECs. (A) Coomassi...
(A) Coomassie blue–stained gel showing a low-molecular-weight band in denatonium-stimulated ASL (representative of 3 gels; 6 patients). (B) Denatonium-stimulated secretions were run through a Centricon filter (30-kDa MWCO); antimicrobial activity was retained in the lower molecular weight fraction. Antibacterial activity was retained when ASL from denatonium-treated cultures was dialyzed against 3-kDa MWCO, was reduced with a 12-kDa MWCO, and was fully lost with a 50-kDa MWCO (n = 3–5 ALIs from at least 3 patients each). (C) Antimicrobial function was inhibited by increasing [NaCl] (n = 7 patients) (significance vs. PBS ASL with same [NaCl]). (D and E) T2R agonists denatonium, absinthin, parthenolide, and amarogentin stimulate secretion of β-defensins 1 (green) and 2 (white) (n = 5–25 cultures from >3 patients each). *P < 0.05; **P < 0.01, compared with PBS ASL, by 1-way ANOVA with Dunnett’s post-test. (F) Intracellular β-defensin decreased after 30-minute stimulation with 10 mM denatonium and returned to baseline levels by 6 days (n = 5 cultures from 5 patients each). (G) Bactericidal activity of denatonium-stimulated ASL was blocked by antibodies to β-defensins (30-minute preincubation) or immunodepletion of β-defensins (n = 5 cultures from 5 patients each). (B, C, and G) *P < 0.05, **P < 0.01, determined by 1-way ANOVA with Bonferroni post-test. (H) Denatonium (10 mM) stimulated β-defensin 1 and 2 secretion by ex vivo human turbinate that was significantly inhibited by 1.5 mM glucose. Defensin concentration normalized per mg of wet-weight tissue. *P < 0.05, **P < 0.01. All data are mean ± SEM.