Taste receptors in innate immunity

Abstract

Taste receptors were first identified on the tongue, where they initiate a signaling pathway that communicates information to the brain about the nutrient content or potential toxicity of ingested foods. However, recent research has shown that taste receptors are also expressed in a myriad of other tissues, from the airway and gastrointestinal epithelia to the pancreas and brain. The functions of many of these extraoral taste receptors remain unknown, but emerging evidence suggests that bitter and sweet taste receptors in the airway are important sentinels of innate immunity. This review discusses taste receptor signaling, focusing on the G-protein-coupled receptors that detect bitter, sweet, and savory tastes, followed by an overview of extraoral taste receptors and in-depth discussion of studies demonstrating the roles of taste receptors in airway innate immunity. Future research on extraoral taste receptors has significant potential for identification of novel immune mechanisms and insights into host-pathogen interactions.

Fig. 1

G-protein coupled receptors (GPCRs) involved in bitter, sweet, and umami taste. a Bitter taste receptors are generally believed to be primarily composed of homo- or hetero-oligomers of isoforms of the taste receptor 2 (T2R) family [, –31]. Most T2R isoforms have been shown to co-immunoprecipitate with other T2R isoforms co-expressed in heterologous expression systems [41, 42]. However, while most bitter responsive type II taste cells express multiple T2Rs, the state of T2R oligomerization in vivo is almost completely unknown. Additionally, the EC₅₀ values for receptors do not appear to be shifted by co-expression of different T2Rs in the same cells, as measured through calcium signaling in heterologous expression systems in vitro [41, 42]. However, potential effects of T2R oligomerization in type II taste cell signaling in vivo are unknown. It remains unclear whether each T2R oligomer signals independently or cooperatively. b, c Umami and sweet receptors are made up of oligomers of the taste receptor 1 (T1R) family. T1R1 and T1R3 oligomers form umami receptors [, –23], while T1R2 and T1R3 oligomers form sweet receptors [–15]. Both T1R and T2R family members are believed to have similar structures to other 7-transmembrane domain GPCRs, but T1Rs are believed to have more extensive extracellular N-termini than do T2Rs. The N-termini of T1Rs are thought to contain multiple ligand binding sites [12, 22, 31, 39, 47]

Fig. 2

Signal transduction pathway of bitter (T2R), sweet (T1R2/3), and umami (T1R1/3) GPCRs in type II taste cells of the tongue. As described in the text and reviewed in [11, 32], ligand binding to taste GPCRs results in Ca²⁺ signaling through two G-protein-coupled pathways. Gβγ activation of phospholipase C isoform β2 (PLCβ2) results in production of inositol 1,4,5-trisphosphate (IP₃), which activates the IP₃ receptor (IP₃R), an intracellular ion channel that allows calcium (Ca²⁺) release from the intracellular endoplasmic reticulum (ER) calcium stores [254]. Simultaneously, Gα-gustducin activates phosophodiesterases (PDEs), which reduce the levels of cyclic-AMP (cAMP) and decrease protein kinase A (PKA) activity [28]. PKA can phosphorylate and inhibit the activity of the type III IP₃R [255, 256], the major IP₃R isoform found in type II taste cells [–259], thus reduction of PKA activity can enhance IP₃R3-mediated calcium signaling. Calcium activates the plasma membrane-localized cation channel TRPM5 [137, 138], causing depolarization of cellular membrane potential, activation of voltage-gated sodium (Na⁺) channels [260], and generation of an action potential that results in ATP release [11] through the CALHM1 ion channel [45, 46] and subsequent purinergic neurotransmission of taste sensations

Fig. 3

Mechanisms of epithelial innate immunity in the airway. As described in the text and reviewed in [105, 261], inhaled viruses, bacteria, and fungi are trapped by sticky mucus created by mucin macromolecules secreted by secretory goblet cells. Trapped pathogens are removed from the airway by mucociliary transport, which is driven by ciliary beating and is dependent upon regulation of ion and fluid transport by epithelial cells that regulates the mucus viscosity. In addition to mucociliary transport, direct pathogen killing or inactivation can occur via the secretion of antimicrobial peptides as well as the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). During longer-term exposure to pathogens, epithelial cells can also secrete cytokines to recruit dedicated immune cells and activate inflammatory pathways

Fig. 4

T2R38 bitter taste receptor regulation of airway epithelial innate immunity. Reading from left to right, acyl-homoserine lactone (AHL) molecules are secreted by gram-negative bacteria to regulate quorum sensing. These AHL molecules activate T2R38 expressed in human sinonasal cilia [81] and yet-unidentified T2Rs in mouse nasal cilia [82], which results in activation of PLCβ2, which liberates IP₃ and causes initiation of a calcium (Ca²⁺) signal that activates nitric oxide synthase (NOS)-dependent nitric oxide (NO) production. Because the NOS activation is rapid (within seconds) and Ca²⁺-dependent, it is likely that the NOS isoforms involved are of the endothelial NOS (eNOS) family [262], known to be expressed in the airway [263]. NO production has two distinct effects. The first is activation of cellular protein kinase G (PKG), which phosphorylates ciliary proteins [129, 264] to increase ciliary beating and mucociliary transport [81, 82]. NO additionally diffuses directly into the airway surface liquid, where it has direct bactericidal effects [81]

Fig. 5

Nasal solitary chemosensory cell (SCC)- and taste receptor-dependent regulation of airway innate immunity. Reading from left to right, bitter chemicals are secreted by microbes during infection. Some of these molecules, which are yet unidentified but are distinct from AHLs, activate the T2R bitter receptors expressed in solitary chemosensory cells (SCCs), which activates a Gα-gustducin (Gα-gust.)-dependent and PLCβ2-dependent calcium (Ca²⁺) response that propagates to surrounding epithelial cells via gap junctions [76]. In human, but not mouse, sinonasal epithelial cells, this calcium signal causes the surrounding cells to secrete antimicrobial peptides (AMPs), including β-defensins, which directly kill both gram-positive and gram-negative bacteria. Airway surface liquid (ASL) glucose (~0.5 mM in healthy individuals [76]) normally attenuates T2R-mediated signaling through activation of T1R2/3 sweet receptors, except during times of infection, when bacteria likely decrease ASL glucose concentration by consuming and metabolizing the glucose. Reduction of ASL glucose relieves the T1R2/3-mediated inhibition of T2R signaling and AMP secretion [76]. In mice, SCC activation by bitter compounds results in acetylcholine (ACh) release and activation of trigeminal neurons [77]; it remains to be determined if this mechanism also exists in the human nasal epithelium. For purposes of simplicity and clarity, T2R receptors present in nasal ciliated cells are not shown in this figure