The Role of Quinine-Responsive Taste Receptor Family 2 in Airway Immune Defense and Chronic Rhinosinusitis.

Nithin D. Adappa,Michael A. Kohanski,Beverly J. Cowart,Alan D. Workman,Noam A. Cohen,David W. Kennedy,Corrine Mansfield,Steven G. Brooks,James N. Palmer,Robert J. Lee,Ivy W. Maina,Danielle R. Reed

doi:10.3389/fimmu.2018.00624

Abstract

Bitter (T2R) and sweet (T1R) taste receptors in the airway are important in innate immune defense, and variations in taste receptor functionality in one T2R (T2R38) correlate with disease status and disease severity in chronic rhinosinusitis (CRS). Quinine is a bitter compound that is an agonist for several T2Rs also expressed on sinonasal cells, but not for T2R38. Because of this property, quinine may stimulate innate immune defense mechanisms in the airway, and functional differences in quinine perception may be reflective of disease status in CRS. Demographic and taste intensity data were collected prospectively from CRS patients and non-CRS control subjects. Sinonasal tissue from patients undergoing rhinologic surgery was also collected and grown at an air-liquid interface (ALI). Nitric oxide (NO) production and dynamic regulation of ciliary beat frequency in response to quinine stimulation were assessed in vitro. Quinine reliably increased ciliary beat frequency and NO production in ALI cultures in a manner consistent with T2R activation (p < 0.01). Quinine taste intensity rating was performed in 328 CRS patients and 287 control subjects demonstrating that CRS with nasal polyps (CRSwNP) patients rated quinine as significantly less intense than did control subjects. Quinine stimulates airway innate immune defenses by increasing ciliary beat frequency and stimulating NO production in a manner fitting with T2R activation. Patient variability in quinine sensitivity is observed in taste intensity ratings, and gustatory quinine "insensitivity" is associated with CRSwNP status. Thus, taste tests for quinine may be a biomarker for CRSwNP, and topical quinine has therapeutic potential as a stimulant of innate defenses.

Highlights

Chronic rhinosinusitis (CRS) is a complex syndrome with a multifactorial etiology of inflammation and infection [1]
At least two quinine-responsive T2Rs are expressed in human sinonasal epithelial cells and in air–liquid interface (ALI) culture [19, 25], and cultures used for the following experiments were shown to express both T2R4 and T2R14 by polymerase chain reaction (Figure S1 in Supplementary Material)
Prior work with T2R38 has revealed a T2R stimulation pathway in ciliated cells that results in nitric oxide (NO) production that has antimicrobial activity [15]

Summary

Introduction

Chronic rhinosinusitis (CRS) is a complex syndrome with a multifactorial etiology of inflammation and infection [1]. Studies have explored the role of airway taste receptors in sinonasal innate immunity, and how functional polymorphisms in these receptors may be implicated in the pathogenesis of CRS [4,5,6,7,8]. Bitter (T2R) and sweet (T1R) taste receptors in the airway are important in innate immune defense, and variations in taste receptor functionality in one T2R (T2R38) correlate with disease status and disease severity in chronic rhinosinusitis (CRS). Quinine is a bitter compound that is an agonist for several T2Rs expressed on sinonasal cells, but not for T2R38 Because of this property, quinine may stimulate innate immune defense mechanisms in the airway, and functional differences in quinine perception may be reflective of disease status in CRS

Methods

Results

Conclusion