Abstract
Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ∼20% of adult antibiotic prescriptions in the United States. Because of the rise of resistant microorganisms, there is a critical need to better understand how to stimulate and/or enhance innate immune responses as a therapeutic modality to treat respiratory infections. We recently identified bitter taste receptors (taste family type 2 receptors, or T2Rs) as important regulators of sinonasal immune responses and potentially important therapeutic targets. Here, we examined the immunomodulatory potential of flavones, a class of flavonoids previously demonstrated to have antibacterial and anti-inflammatory effects. Some flavones are also T2R agonists. We found that several flavones inhibit Muc5AC and inducible NOS up-regulation as well as cytokine release in primary and cultured airway cells in response to several inflammatory stimuli. This occurs at least partly through inhibition of protein kinase C and receptor tyrosine kinase activity. We also demonstrate that sinonasal ciliated epithelial cells express T2R14, which closely co-localizes (<7 nm) with the T2R38 isoform. Heterologously expressed T2R14 responds to multiple flavones. These flavones also activate T2R14-driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance. TAS2R38 polymorphisms encode functional (PAV: proline, alanine, and valine at positions 49, 262, and 296, respectively) or non-functional (AVI: alanine, valine, isoleucine at positions 49, 262, and 296, respectively) T2R38. Our data demonstrate that T2R14 in sinonasal cilia is a potential therapeutic target for upper respiratory infections and that flavones may have clinical potential as topical therapeutics, particularly in T2R38 AVI/AVI individuals.
Highlights
Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ϳ20% of adult antibiotic prescriptions in the United States
Chronic rhinosinusitis (CRS)2 is a syndrome of chronic inflammation and/or infection of the upper respiratory tract, which leads to substantial decreases in patient quality of life, creates Ͼ$8 billion in direct healthcare costs in the United States alone, and can seed lower respiratory infections and exacerbate lung diseases [1,2,3]
We found that patients homozygous for a polymorphism in the TAS2R38 gene resulting in non-functional T2R38 protein (the AVI polymorphism [32]) are more susceptible to Gram-negative bacterial infection [27], have a higher incidence of biofilm-forming bacteria [33], are at higher risk for CRS requiring functional endoscopic sinus surgery (FESS) [34, 35], and may have worse outcomes after FESS for CRS without nasal polyps [36] compared with patients homozygous for the functional (PAV: proline, alanine, and valine at positions 49, 262, and 296, respectively) allele of TAS2R38
Summary
Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ϳ20% of adult antibiotic prescriptions in the United States. These flavones activate T2R14driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance. An attractive therapeutic strategy to avoid the selective pressures for antibiotic resistance is to stimulate endogenous innate host defenses This requires a better understanding of the receptors involved in activating upper airway innate immunity. We previously showed that a bitter “taste” G-protein-coupled receptor, T2R38, is expressed in the motile cilia of cells of the upper airway (nose and sinuses) and modulates mucociliary clearance through calcium (Ca2ϩ)-dependent production of nitric oxide (NO) [2, 22,23,24,25,26,27]. There are 25 different T2R bitter receptors in humans [22, 24, 37, 38], and other researchers have confirmed that polymorphisms in at least two TAS2R genes, TAS2R38 and TAS2R13, correlate with CRS by genome-wide association [39]
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