scholarly journals Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

2019 ◽  
Author(s):  
Indiwari Gopallawa ◽  
Jenna R. Freund ◽  
Robert J. Lee
Keyword(s):  
Nitric Oxide ◽  
Epithelial Cells ◽  
Bitter Taste ◽  
The Body ◽  
Cell Physiology ◽  
No Production ◽  
Taste Receptors ◽  
Calcium Signals ◽  
Low Level ◽  
Bitter Taste Receptors

AbstractBitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (MΦs) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis ∼3-fold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance MΦ phagocytosis. Together, these data define MΦ T2R signal transduction and support an immune recognition role for T2Rs in MΦ cell physiology.

scholarly journals Nitric Oxide Production is Stimulated by Bitter Taste Receptors Ubiquitously Expressed in the Sinonasal Cavity

2017 ◽  
Vol 31 (2) ◽  
pp. 85-92 ◽  
Author(s):  
Carol H. Yan ◽  
Samuel Hahn ◽  
Derek McMahon ◽  
David Bonislawski ◽  
David W. Kennedy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bitter Taste ◽  
Middle Turbinate ◽  
Immune Defense ◽  
Sinus Surgery ◽  
No Production ◽  
Taste Receptors ◽  
Dependent Manner ◽  
Innate Defense ◽  
Bitter Taste Receptors

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.

scholarly journals Activation of airway epithelial bitter taste receptors byPseudomonas aeruginosaquinolones modulates calcium, cyclic-AMP, and nitric oxide signaling

2018 ◽  
Vol 293 (25) ◽  
pp. 9824-9840 ◽  
Author(s):  
Jenna R. Freund ◽  
Corrine J. Mansfield ◽  
Laurel J. Doghramji ◽  
Nithin D. Adappa ◽  
James N. Palmer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cyclic Amp ◽  
Bitter Taste ◽  
Taste Receptors ◽  
Airway Epithelial ◽  
Nitric Oxide Signaling ◽  
Bitter Taste Receptors

scholarly journals Neuropeptide Y Reduces Nasal Epithelial T2R Bitter Taste Receptor–Stimulated Nitric Oxide Production

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3392
Author(s):  
Ryan M. Carey ◽  
Nithin D. Adappa ◽  
James N. Palmer ◽  
Robert J. Lee
Keyword(s):  
Nitric Oxide ◽  
Neuropeptide Y ◽  
Bitter Taste ◽  
Beat Frequency ◽  
Taste Receptor ◽  
Ciliary Beat Frequency ◽  
Fluid Secretion ◽  
The Body ◽  
No Production ◽  
Neuropeptide Tyrosine

Bitter taste receptors (T2Rs) are G-protein-coupled receptors (GPCRs) expressed on the tongue but also in various locations throughout the body, including on motile cilia within the upper and lower airways. Within the nasal airway, T2Rs detect secreted bacterial ligands and initiate bactericidal nitric oxide (NO) responses, which also increase ciliary beat frequency (CBF) and mucociliary clearance of pathogens. Various neuropeptides, including neuropeptide tyrosine (neuropeptide Y or NPY), control physiological processes in the airway including cytokine release, fluid secretion, and ciliary beating. NPY levels and/or density of NPYergic neurons may be increased in some sinonasal diseases. We hypothesized that NPY modulates cilia-localized T2R responses in nasal epithelia. Using primary sinonasal epithelial cells cultured at air–liquid interface (ALI), we demonstrate that NPY reduces CBF through NPY2R activation of protein kinase C (PKC) and attenuates responses to T2R14 agonist apigenin. We find that NPY does not alter T2R-induced calcium elevation but does reduce T2R-stimulated NO production via a PKC-dependent process. This study extends our understanding of how T2R responses are modulated within the inflammatory environment of sinonasal diseases, which may improve our ability to effectively treat these disorders.

scholarly journals Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1317 ◽  
Author(s):  
Appalaraju Jaggupilli ◽  
Ryan Howard ◽  
Rotimi E. Aluko ◽  
Prashen Chelikani
Keyword(s):  
Advanced Glycation End Products ◽  
Bitter Taste ◽  
The Body ◽  
Taste Perception ◽  
Taste Receptors ◽  
Binding Affinities ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Bitter Taste Receptors

Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception. Advanced glycation end-products (AGEs) are produced by glycation of amino acids in proteins. There are varying sources of AGEs, including dietary food products, as well as endogenous reactions within our body. Whether these AGEs are T2R ligands remains to be characterized. In this study, we selected two AGEs, namely, glyoxal-derived lysine dimer (GOLD) and carboxymethyllysine (CML), based on their predicted interaction with the well-studied T2R4, and its physiochemical properties. Results showed predicted binding affinities (Kd) for GOLD and CML towards T2R4 in the nM and μM range, respectively. Calcium mobilization assays showed that GOLD inhibited quinine activation of T2R4 with IC50 10.52 ± 4.7 μM, whilst CML was less effective with IC50 32.62 ± 9.5 μM. To characterize whether this antagonism was specific to quinine activated T2R4 or applicable to other T2Rs, we selected T2R14 and T2R20, which are expressed at significant levels in different human tissues. A similar effect of GOLD was observed with T2R14; and in contrast, GOLD and CML activated T2R20 with an EC50 of 79.35 ± 29.16 μM and 65.31 ± 17.79 μM, respectively. In this study, we identified AGEs as novel T2R ligands that caused either activation or inhibition of different T2Rs.

scholarly journals Extraoral bitter taste receptors in health and disease

2017 ◽  
Vol 149 (2) ◽  
pp. 181-197 ◽  
Author(s):  
Ping Lu ◽  
Cheng-Hai Zhang ◽  
Lawrence M. Lifshitz ◽  
Ronghua ZhuGe
Keyword(s):  
Innate Immunity ◽  
Bitter Taste ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Taste Perception ◽  
Taste Receptors ◽  
Human Disorders ◽  
Health And Disease ◽  
Bitter Taste Receptors ◽  
G Protein Coupled

Bitter taste receptors (TAS2Rs or T2Rs) belong to the superfamily of seven-transmembrane G protein–coupled receptors, which are the targets of >50% of drugs currently on the market. Canonically, T2Rs are located in taste buds of the tongue, where they initiate bitter taste perception. However, accumulating evidence indicates that T2Rs are widely expressed throughout the body and mediate diverse nontasting roles through various specialized mechanisms. It has also become apparent that T2Rs and their polymorphisms are associated with human disorders. In this review, we summarize the physiological and pathophysiological roles that extraoral T2Rs play in processes as diverse as innate immunity and reproduction, and the major challenges in this emerging field.

scholarly journals Neural Transmission from Oropharyngeal Bitter Receptors to the Medulla is Partially or Completely Labelled-Line

2016 ◽  
Vol 11 (8) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Michael K McMullen
Keyword(s):  
Bitter Taste ◽  
Cell Receptor ◽  
Cell Physiology ◽  
Taste Receptors ◽  
Neural Pathways ◽  
Cephalic Phase ◽  
Autonomic Reflexes ◽  
Neural Transmission ◽  
Bitter Taste Receptors ◽  
The Impact

The ground breaking advances in taste cell receptor cell physiology over the last 20 years have established a functional basis which enables neural pathways to be mapped. There is only one, or perhaps several, types of taste receptors for salt, sour, sweet and umami (meaty) tastes and stimulation of each receptor type elicits responses in different cognitive regions. These findings support the labelled-line neural pathway model. In contrast, there are 25 types of the bitter taste receptors which all produce the same cognitive sensation, a finding which supports the across-fiber pattern model. This paper compiles the findings of several human studies investigating the impact of bitter tastants on postprandial hemodynamics, to demonstrate that diverse bitter tastants are capable of eliciting a range of characteristic reflex cephalic phase responses in the autonomic and cardiovascular systems. These findings indicate that neural pathways from the oropharyngeal bitter taste receptors to the nucleus of the solitary tract are either partially or completely labelled-line. Consequently, the hedonics of a bitter tastant are not an accurate indicator of the cephalic phase responses elicited by the tastant. The finding that secondary metabolites present in dietary condiments modulate autonomic activity and in particular postprandial hemodynamics is novel and adds a new dimension to our understanding of the ways in which humans are influenced by their diet, both in health and disease. These findings suggest that condiments play a role in food digestion, unrelated to their hedonistic qualities. Consequently, condiments may be of significance to those with digestive disorders and especially for diabetics experiencing gastroparesis and/or postprandial hypotension. Additionally, the findings suggest a noninvasive method to assess the integrity of multiple neural pathways. For investigators exploring the effect of condiments on autonomic reflexes, traditional cuisines may be a valuable source as they are full of uncharted human recordings.

scholarly journals HSP90 function is required for T2R bitter taste receptor nitric oxide production and innate immune responses in human airway epithelial cells and macrophages

2021 ◽  
Author(s):  
Ryan M Carey ◽  
Benjamin M Hariri ◽  
Nithin D Adappa ◽  
James N Palmer ◽  
Robert J Lee
Keyword(s):  
Nitric Oxide ◽  
Epithelial Cells ◽  
Bitter Taste ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Innate Immune ◽  
No Production ◽  
Airway Epithelial ◽  
Primary Monocyte ◽  
Hsp 90

Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two airway innate immune cell types are activated by bitter products, including those secreted by common airway pathogens like Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO production leads to enhanced mucociliary clearance and direct antibacterial effects by ciliated epithelial cells as well as increased phagocytosis by macrophages. Using biochemistry and live cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). We used immunofluorescence to show that H441 cells express eNOS and certain T2Rs and that the bitterant denatonium benzoate activates NO production in an HSP90-dependent manner in cells grown either as submerged cultures and at air liquid interface. In primary sinonasal epithelial cells, we determined that HSP-90 inhibition reduces T2R-stimulated NO production and ciliary beating which are crucial for pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves an innate immune role by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream calcium signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases like chronic rhinosinusitis, asthma, or cystic fibrosis.

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