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Background: 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. Methods: 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. results: 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. conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Bitter taste receptors (T2R) have recently been demonstrated to contribute to sinonasal innate immunity. One T2R, T2R38, regulates mucosal defense against gram-negative organisms through nitric oxide (NO) production, which enhances mucociliary clearance and directly kills bacteria. To determine whether additional T2Rs contribute to this innate defense, we evaluated two other sinonasal T2Rs (T2R4 and T2R16) for regulation of NO production and expression within the human sinonasal cavity. Methods: Primary human sinonasal cultures were stimulated with ligands specific to T2R4 and T2R16, colchicine and D-salicin, respectively. Cellular NO production was measured by intracellular 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate fluorescence. For T2R expression mapping, sinonasal tissue was obtained from patients who underwent sinus surgery of the middle turbinate, maxillary sinus, ethmoid sinus, or sphenoid sinus. The expression of T2R4, T2R16, and T2R38 was evaluated by using immunofluorescence with validated antibodies. Results: Similar to T2R38, T2R4 and T2R16 trigger NO production in a dose-dependent manner by using the canonical taste signaling pathway in response to stimulation with their respective ligands. All three receptors were expressed in the cilia of human epithelial cells of all regions in the sinonasal cavity. Conclusion: These three T2Rs signaled through the same NO-mediated antimicrobial pathway and were ubiquitously expressed in the sinonasal epithelium. Additional T2Rs besides T2R38 may play a role in sinonasal immune defense. Mapping of T2R expression demonstrated the potential widespread role of T2Rs in sinonasal defense, whereas the genetics of these T2Rs may contribute to our understanding of specific endotypes of chronic rhinosinusitis and develop into novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background Antimicrobial peptides (AMPs) produced by the epithelium are important for innate immune defense. In 2001, a novel AMP dermcidin (DCD) was described with no homology to other AMPs and an expression pattern restricted to eccrine sweat glands. In contrast to other AMPs, DCD expression has not been shown to be induced under inflammatory conditions in the skin. After identifying DCD by mass spectrometry in a protein sample isolated from human nasal secretions, we sought to determine the role of DCD in innate defense of the sinonasal airway. Methods After institutional review board approval, sinonasal mucosal tissue specimens were acquired from residual clinical material obtained during sinonasal surgery and used to grow cultures in an air-liquid interface environment. After stimulation of the cultures with various bitter compounds and phosphate-buffered saline, airway surface liquid was collected, and a DCD-specific enzyme-linked immunoassay was used to quantify DCD in each sample. To localize DCD expression, ALI cultures were fixed and immunofluorescence performed against DCD, β-tubulin IV, and Muc-5A. Results Enzyme-linked immunoassay showed DCD in air-surface liquid and in clinical nasal secretion samples at concentrations comparable to eccrine sweat. There was no evidence of inducible expression with any of the tested stimulants. Confocal microscopy revealed DCD expression in sinonasal mucosal goblet cells. Conclusion This is the first report of the presence of DCD in nasal mucosa and demonstration of DCD in clinical samples of human nasal secretions at clinically relevant concentrations, which may represent a novel arm of sinonasal airway innate defense. [ABSTRACT FROM AUTHOR]