The role of bitter and sweet taste receptors in upper airway innate immunity: Recent advances and future directions

Abstract

Bitter (T2R) and sweet (T1R) taste receptors have been implicated in sinonasal innate immunity and in the pathophysiology of chronic rhinosinusitis (CRS). Taste receptors are expressed on several sinonasal cell types including ciliated epithelial cells and solitary chemosensory cells. Bitter agonists released by pathogenic microbes elicit a T2R dependent signaling cascade which induces the release of bactericidal nitric oxide, increases mucociliary clearance, and promotes secretion of antimicrobial peptides. Genetic variation conferred by polymorphisms in T2R related genes is associated with differential CRS susceptibility, symptomatology and post-treatment outcomes. More recently, based on our understanding of T1R and T2R function, investigators have discovered novel potential therapeutics in T2R agonists and T1R antagonists. This review will discuss bitter and sweet taste receptor function in sinonasal immunity, explore the emerging diagnostic and therapeutic implications stemming from the most recent findings, and suggest directions for future research.

Keywords: Bitter taste receptors; Chronic rhinosinusitis; Innate immunity; Polymorphism; Solitary chemosensory cells; Sweet taste receptors; Taste Receptor Family 1 (T1R); Taste Receptor Family 2 (T2R).

Fig. 1

T2R38-mediated regulation of sinonasal immunity. Bacterial species like P. aeruginosa release quorum sensing molecules like acyl-homoserine lactones (AHLs) and quinolones. These bitter microbial products activate T2R38 and elicit a local immune response via the canonical taste-signaling pathway. This response involves activation of PLCβ2 and IP₃ production. IP₃ triggers the release of calcium (Ca²⁺) from the endoplasmic reticulum (ER). Increase in intracellular Ca²⁺ concentration activates nitric oxide (NO) formation via nitric oxide synthase (NOS). NO increases ciliary beat frequency via activation of protein kinase G and diffuses into the airway surface liquid to directly kill bacteria.

Fig. 2

Bitter and sweet taste receptors on solitary chemosensory cells act antagonistically to regulate innate immunity. Activation of bitter T2R receptors leads to downstream increase in intracellular Ca²⁺ concentration. Ca²⁺ spreads to neighboring ciliated cells via gap junctions and activates the release of anti-microbial peptides (AMPs), directly killing pathogenic microbes. Activation of the sweet receptor T1R (dimer of T1R2 and T1R3) by sweet tasting compounds like glucose inhibits this Ca²⁺ mediated response. Microbial consumption of glucose decreases stimulation of the T1R receptor thereby disinhibiting the T2R response to microbial bitter products.

Fig. 3

SCCs produce IL-25 with SCC proliferation and increased IL25 levels evident in nasal polyps. IL-25, in conjunction with other epithelial derived cytokines (IL-33 and TSLP), stimulates an eosinophilic type 2 inflammatory response via the activation and proliferation of group-2 innate lymphoid cells (ILC-2s). IL-13 released by ILC2s induces SCC proliferation in a feed-forward fashion while this IL-13 induced SCC proliferation is inhibited by corticosteroid exposure.