Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

J Biol Chem. 2017 May 19;292(20):8484-8497. doi: 10.1074/jbc.M116.771949. Epub 2017 Apr 3.

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.

Keywords: airway surface liquid; antimicrobial peptide (AMP); bitter taste receptor; chronic rhinosinusitis; flavonoid; innate immunity; mucociliary clearance; nitric oxide; polyphenol; protein kinase C (PKC).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Anti-Inflammatory Agents / pharmacology*
  • Flavones / pharmacology*
  • Humans
  • Immunity, Innate / drug effects*
  • Immunity, Innate / genetics
  • Mucin 5AC / genetics
  • Mucin 5AC / immunology
  • Nasal Mucosa / immunology*
  • Nitric Oxide / genetics
  • Nitric Oxide / immunology
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / immunology*
  • Polymorphism, Genetic
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / immunology*

Substances

  • Anti-Inflammatory Agents
  • Flavones
  • MUC5AC protein, human
  • Mucin 5AC
  • Receptors, G-Protein-Coupled
  • taste receptors, type 2
  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II