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 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 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

Bitter Taste Receptors, T2R138 and T2R16, are Induced in the Large Intestine of Male and Female Mice on a High Fat Diet in a Microbiota-Dependent Manner

2017 ◽  
Vol 152 (5) ◽  
pp. S156
Author(s):  
Filippo Caremoli ◽  
Jennifer Huynh ◽  
Venu Lagishetty ◽  
Jonathan Jacobs ◽  
Jonathan Braun ◽  
...  
Keyword(s):  
Large Intestine ◽  
High Fat Diet ◽  
Bitter Taste ◽  
Taste Receptors ◽  
Dependent Manner ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Bitter Taste Receptors

scholarly journals Sinonasal T2R-Mediated Nitric Oxide Production in Response to Bacillus Cereus

2017 ◽  
Vol 31 (4) ◽  
pp. 211-215 ◽  
Author(s):  
Ryan M. Carey ◽  
Alan D. Workman ◽  
Carol H. Yan ◽  
Bei Chen ◽  
Nithin D. Adappa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bacillus Cereus ◽  
Signaling Pathway ◽  
Airway Epithelium ◽  
Bitter Taste ◽  
Beat Frequency ◽  
Upper Airway ◽  
No Production ◽  
Gram Positive ◽  
Innate Defense

Background Upper airway epithelial cells produce bactericidal nitric oxide (NO) in response to both gram-positive and gram-negative bacteria. Our previous work demonstrated that T2R38, a bitter taste receptor (T2R) expressed in airway epithelium, produces NO in response to quorum-sensing molecules secreted by Pseudomonas aeruginosa. We also demonstrated that Staphylococci products elicit an NO response when using a T2R-independent pathway. When screening additional human pathogens for epithelial T2R activation, we found that the gram-positive aerobe Bacillus cereus secretes a T2R agonist that yields NO production. Objective The objective of this study was to characterize the activating B. cereus product(s) and to describe the epithelial cell signaling pathway involved. Methods Sinonasal air-liquid interface cultures were treated with B. cereus conditioned medium (CM), and NO production was measured by using 4-amino-5-methylamino-2′,7′ -difluorofluorescein fluorescence imaging. Ciliary beat frequency (CBF) was assessed in response to B. cereus CM. Pharmacologic studies that use inhibitors of the T2R-signaling pathway were used to determine if the production of NO was mediated by a T2R. Purification studies were performed to analyze the physical properties of the activating product(s) contained in the CM. Results A product(s) secreted by B. cereus induced NO production and increased CBF. The response varied markedly between individual patients and involved two important components of bitter taste signaling, phospholipase C isoform β-2 and the transient receptor potential melastatin isoform 5 ion channel. Conclusions This study demonstrated that a B. cereus product(s) elicited an NO-mediated innate defense response in upper airway epithelium that seemed to be partially mediated by a T2R signaling pathway. The active product that elicited the NO response was likely a small nonpeptide compound, but further purification is required for identification. Patient variation in the NO response to B. cereus products could potentially be due to genetic differences in T2Rs.

The correlation of TAS2R38 gene variants with higher risk for chronic rhinosinusitis in Polish patients

2016 ◽  
Vol 70 (5) ◽  
pp. 13-18 ◽  
Author(s):  
Karolina Dżaman ◽  
Mariola Zagor ◽  
Elżbieta Sarnowska ◽  
Antoni Krzeski ◽  
Ireneusz Kantor
Keyword(s):  
Chronic Rhinosinusitis ◽  
Bitter Taste ◽  
Respiratory Infections ◽  
Geographic Region ◽  
Sinus Surgery ◽  
Taste Receptors ◽  
Nucleotide Polymorphisms ◽  
Tas2r38 Gene ◽  
Preliminary Study ◽  
Bitter Taste Receptors

Background: Bitter taste receptors (T2Rs), especially T2R38s appear as innovative regulators of innate immunity in the respiratory system. The single nucleotide polymorphisms (SNPs) in TAS2R38 gene may contribute to individual differences in susceptibility to respiratory infections especially chronic rhinosinusitis (CRS). TAS2R38 genotypes distribution varies by geographic region, race and ethnicity. The aim of the preliminary study was the identification of SNPs in TAS2R38 encoding genes in Polish patients with CRS and finding potential correlation with CRS phenotypes. Material and methods: The preliminary study contained 20 CRS patients undergoing functional endoscopic sinus surgery (FESS). Fresh sinus mucosa (SM) was obtained during FESS in CRS patients. Patients were genotyped for TAS2R38 using Sanger method and the genotype occurrences of the clinically recalcitrant CRS cohort was evaluated. Analysis of TAS2R38 expression in SM of CRS patients was performed using immunohistochemistry (IHC). Results: T2R38 was highly expressed in SM of CRS patients. Patients with CRS demonstrated both common genotypes PAV, AVI. The heterozygotes frequency (AVI/PAV) was the highest. The protective genotype (PAV/PAV) was noticed in the lowest frequency and connected with lower average value of CT score compare to AVI/AVI genotypes (p=0.01). Conclusions: The work presented in this study provides the hypothesis that airway bitter T2Rs are an innovative sphere of human respiratory innate protection. TAS2R38 polymorphism may influence the susceptibility to CRS. The AVI haplotypes are an independent risk factors for CRS. Additionally, the bitter taste receptors and related signalling pathways might create an unique group of therapeutic targets to treat CRS.

scholarly journals 3-oxo-C12:2-HSL, Quorum Sensing Molecule from Human Intestinal Microbiota, Inhibits Pro-inflammatory Pathways in Immune Cells via Bitter Taste Receptors

2022 ◽  
Author(s):  
Garance Coquant ◽  
Doriane Aguanno ◽  
Loic Brot ◽  
Christine Belloir ◽  
Julie Delugeard ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Bitter Taste ◽  
Molecular System ◽  
Raw264.7 Cells ◽  
Signalling Pathways ◽  
Taste Receptors ◽  
Dependent Manner ◽  
Screening Assay ◽  
Bitter Taste Receptors ◽  
Anti Inflammatory

Abstract In the gut ecosystem, microorganisms regulate group behaviour and interplay with the host via a molecular system called quorum sensing (QS). The QS molecule 3-oxo-C12:2-HSL, first identified in human gut microbiota, exerts anti-inflammatory effects and could play a role in inflammatory bowel diseases where dysbiosis has been described. Our aim was to identify which signalling pathways are involved in this effect. We observed that 3-oxo-C12:2-HSL decreases expression of pro-inflammatory cytokines such as, Interleukine-1β (-3 %) and Tumor Necrosis Factor-α (TNFα) (40 %) by stimulated immune RAW264.7 cells and decreased TNF secretion by stimulated PBMC in a dose-dependent manner, between 25 µM to 100 µM. Transcriptomic analysis of RAW264.7 cells exposed to 3-oxo-C12:2-HSL, in a pro-inflammatory context, highlighted JAK-STAT, NF-κB and TFN signalling pathways and we confirmed that 3-oxo-C12:2-HSL inhibited JAK1 and STAT1 phosphorylation. We also showed through a screening assay that 3-oxo-C12:2-HSL interacted with several human bitter taste receptors. Its anti-inflammatory effect involved TAS2R38 as shown by pharmacologic inhibition and led to an increase in intracellular calcium levels. We thus unravelled the involvement of several cellular pathways in the anti-inflammatory effects exerted by the QS molecule 3-oxo-C12:2-HSL.

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