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Miller ZA, Carey RM, Lee RJ. A deadly taste: linking bitter taste receptors and apoptosis. Apoptosis 2025; 30:674-692. [PMID: 39979526 PMCID: PMC11946974 DOI: 10.1007/s10495-025-02091-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 02/22/2025]
Abstract
Humans can perceive five canonical tastes: salty, sour, umami, sweet, and bitter. These tastes are transmitted through the activation of ion channels and receptors. Bitter taste receptors (Taste Family 2 Receptors; T2Rs) are a sub-family of 25 G-protein coupled receptor (GPCR) isoforms that were first identified in type II taste bud cells. T2Rs are activated by a broad array of bitter agonists, which cause an increase in intracellular calcium (Ca2+) and a decrease in cyclic adenosine 3',5'-monophosphate (cAMP). Interestingly, T2Rs are expressed beyond the oral cavity, where they play diverse non-taste roles in cell physiology and disease. Here, we summarize the literature that explores the role of T2Rs in apoptosis. Activation of T2Rs with bitter agonists induces apoptosis in several cancers, the airway epithelia, smooth muscle, and more. In many of these tissues, T2R activation causes mitochondrial Ca2+ overload, a main driver of apoptosis. This response may be a result of T2R cellular localization, nuclear Ca2+ mobilization and/or a remnant of the established immunological roles of T2Rs in other cell types. T2R-induced apoptosis could be pharmacologically leveraged to treat diseases of altered cellular proliferation. Future work must explore additional extra-oral T2R-expressing tissues for apoptotic responses, develop methods for in-vivo studies, and discover high affinity bitter agonists for clinical application.
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Affiliation(s)
- Zoey A Miller
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Pharmacology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ryan M Carey
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Robert J Lee
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
- Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
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Mei H, Qi C, Liu J, Yang S, Zhou J, Lu Y, Zheng L, Li J, Zhao L, Xu X. hTAS2R38 polymorphisms modulate oral microbiota and influence the prevalence and treatment outcome of halitosis. MICROBIOME 2025; 13:85. [PMID: 40156025 PMCID: PMC11951550 DOI: 10.1186/s40168-025-02087-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 03/10/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND The genetic susceptibility of halitosis is unclear, challenging its precise management in high-risk population. Here we investigated the association of hTAS2R38 polymorphisms with the prevalence and treatment outcome of halitosis, with a particular focus on oral microbiota. METHODS A cross-sectional study including 689 participants was conducted to investigate the association between hTAS2R38 polymorphisms and halitosis. A 6-month cohort including 60 halitosis patients was established to explore the relationship between hTAS2R38 polymorphisms and treatment outcome of halitosis. Salivary microbiota was further analyzed and its correlation with hTAS2R38 polymorphisms was investigated. RESULTS In the cross-sectional study, a higher prevalence of halitosis was observed in individuals with AVI/AVI genotype as compared to non-AVI/AVI genotype (PAV/PAV + PAV/AVI) (OR = 2.380, 95% CI = 1.493-3.807). 16S rRNA sequencing revealed the enrichment of Prevotella in the saliva of AVI/AVI individuals. In the prospective study, halitosis patients with AVI/AVI genotype exhibited poor treatment outcome relative to non-AVI/AVI individuals during the 6-month follow-up after halitosis intervention (RR = 2.077, 95% CI = 1.382-3.339). Tannerella, Filifactor, and Mycoplasma were identified to be the major persistent genus in the saliva of AVI/AVI patients over the 6-month period after treatment. Furthermore, the human gingival fibroblasts with AVI/AVI genotype exhibited reduced inhibition against the growth and volatile sulfur compounds production of periodontal pathogens. CONCLUSIONS Our work demonstrates that hTAS2R38 polymorphisms contribute to the development and treatment outcome of halitosis via modulating oral microbiota, providing new insights to the better management of halitosis. Video Abstract.
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Affiliation(s)
- Hongxiang Mei
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Cai Qi
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jinchi Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Sirui Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Shaanxi Key Laboratory of Stomatology, Department of Operative Dentistry and Endodontics, School of Stomatology, National Clinical Research Center for Oral Diseases, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jiajia Zhou
- School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yangyu Lu
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guangdong Provincial Clinical Research Center of Oral Diseases, Sun Yat-Sen University, Guangzhou, China
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Juan Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Lei Zhao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
- Department of Periodontology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - Xin Xu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
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Behrens M. International Union of Basic and Clinical Pharmacology. CXVII: Taste 2 receptors-Structures, functions, activators, and blockers. Pharmacol Rev 2025; 77:100001. [PMID: 39952694 DOI: 10.1124/pharmrev.123.001140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 06/20/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
For most vertebrates, bitter perception plays a critical role in the detection of potentially harmful substances in food items. The detection of bitter compounds is facilitated by specialized receptors located in the taste buds of the oral cavity. This work focuses on these receptors, including their sensitivities, structure-function relationships, agonists, and antagonists. The existence of numerous bitter taste receptor variants in the human population and the fact that several of them profoundly affect individual perceptions of bitter tastes are discussed as well. Moreover, the identification of bitter taste receptors in numerous tissues outside the oral cavity and their multiple proposed roles in these tissues are described briefly. Although this work is mainly focused on human bitter taste receptors, it is imperative to compare human bitter taste with bitter taste of other animals to understand which forces might have shaped the evolution of bitter taste receptors and their functions and to distinguish apparently typical human features from rather general ones. For readers who are not very familiar with the gustatory system, short descriptions of taste anatomy, signal transduction, and oral bitter taste receptor expression are included in the beginning of this article. SIGNIFICANCE STATEMENT: Apart from their role as sensors for potentially harmful substances in the oral cavity, the numerous additional roles of bitter taste receptors in tissues outside the gustatory system have recently received much attention. For careful assessment of their functions inside and outside the taste system, a solid knowledge of the specific and general pharmacological features of these receptors and the growing toolbox available for studying them is imperative and provided in this work.
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Affiliation(s)
- Maik Behrens
- Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.
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Grădinaru TC, Vlad A, Gilca M. Bitter Phytochemicals as Novel Candidates for Skin Disease Treatment. Curr Issues Mol Biol 2023; 46:299-326. [PMID: 38248322 PMCID: PMC10814078 DOI: 10.3390/cimb46010020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/21/2023] [Accepted: 12/26/2023] [Indexed: 01/23/2024] Open
Abstract
Skin diseases represent a global healthcare challenge due to their rising incidence and substantial socio-economic burden. While biological, immunological, and targeted therapies have brought a revolution in improving quality of life and survival rates for certain dermatological conditions, there remains a stringent demand for new remedies. Nature has long served as an inspiration for drug development. Recent studies have identified bitter taste receptors (TAS2Rs) in both skin cell lines and human skin. Additionally, bitter natural compounds have shown promising benefits in addressing skin aging, wound healing, inflammatory skin conditions, and even skin cancer. Thus, TAS2Rs may represent a promising target in all these processes. In this review, we summarize evidence supporting the presence of TAS2Rs in the skin and emphasize their potential as drug targets for addressing skin aging, wound healing, inflammatory skin conditions, and skin carcinogenesis. To our knowledge, this is a pioneering work in connecting information on TAS2Rs expression in skin and skin cells with the impact of bitter phytochemicals on various beneficial effects related to skin disorders.
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Affiliation(s)
- Teodora-Cristiana Grădinaru
- Department of Functional Sciences I/Biochemistry, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (T.-C.G.); (M.G.)
| | - Adelina Vlad
- Department of Functional Sciences I/Physiology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Marilena Gilca
- Department of Functional Sciences I/Biochemistry, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (T.-C.G.); (M.G.)
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Posta E, Fekete I, Gyarmati E, Stündl L, Zold E, Barta Z. The Effects of Artificial Sweeteners on Intestinal Nutrient-Sensing Receptors: Dr. Jekyll or Mr. Hyde? Life (Basel) 2023; 14:10. [PMID: 38276259 PMCID: PMC10817473 DOI: 10.3390/life14010010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 01/27/2024] Open
Abstract
The consumption of artificial and low-calorie sweeteners (ASs, LCSs) is an important component of the Western diet. ASs play a role in the pathogenesis of metabolic syndrome, dysbiosis, inflammatory bowel diseases (IBDs), and various inflammatory conditions. Intestinal nutrient-sensing receptors act as a crosstalk between dietary components, the gut microbiota, and the regulation of immune, endocrinological, and neurological responses. This narrative review aimed to summarize the possible effects of ASs and LCSs on intestinal nutrient-sensing receptors and their related functions. Based on the findings of various studies, long-term AS consumption has effects on the gut microbiota and intestinal nutrient-sensing receptors in modulating incretin hormones, antimicrobial peptides, and cytokine secretion. These effects contribute to the regulation of glucose metabolism, ion transport, gut permeability, and inflammation and modulate the gut-brain, and gut-kidney axes. Based on the conflicting findings of several in vitro, in vivo, and randomized and controlled studies, artificial sweeteners may have a role in the pathogenesis of IBDs, functional bowel diseases, metabolic syndrome, and cancers via the modulation of nutrient-sensing receptors. Further studies are needed to explore the exact mechanisms underlying their effects to decide the risk/benefit ratio of sugar intake reduction via AS and LCS consumption.
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Affiliation(s)
- Edit Posta
- GI Unit, Department of Infectology, Faculty of Medicine, University of Debrecen, Bartok Bela Street 2-26, 4031 Debrecen, Hungary; (E.G.); (Z.B.)
| | - Istvan Fekete
- Institute of Food Technology, Faculty of Agricultural and Food Sciences and Environmental Management, University of Debrecen, Böszörményi út 138, 4032 Debrecen, Hungary; (I.F.); (L.S.)
| | - Eva Gyarmati
- GI Unit, Department of Infectology, Faculty of Medicine, University of Debrecen, Bartok Bela Street 2-26, 4031 Debrecen, Hungary; (E.G.); (Z.B.)
- Doctoral School of Clinical Immunology and Allergology, Faculty of Medicine, University of Debrecen, Nagyerdei Blvd. 98, 4032 Debrecen, Hungary
| | - László Stündl
- Institute of Food Technology, Faculty of Agricultural and Food Sciences and Environmental Management, University of Debrecen, Böszörményi út 138, 4032 Debrecen, Hungary; (I.F.); (L.S.)
| | - Eva Zold
- Department of Clinical Immunology, Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, Móricz Zsigmond Str. 22, 4032 Debrecen, Hungary;
| | - Zsolt Barta
- GI Unit, Department of Infectology, Faculty of Medicine, University of Debrecen, Bartok Bela Street 2-26, 4031 Debrecen, Hungary; (E.G.); (Z.B.)
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Luscombe VB, Baena-López LA, Bataille CJR, Russell AJ, Greaves DR. Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84. Eur J Pharmacol 2023; 956:175960. [PMID: 37543157 PMCID: PMC10804997 DOI: 10.1016/j.ejphar.2023.175960] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023]
Abstract
GPR84 is an orphan G-protein coupled receptor (GPCR) linked to inflammation. Strategies targeting GPR84 to prevent excessive inflammation in disease are hampered by a lack of understanding of its precise functional role. We have developed heterologous cell lines with low GPR84 expression levels that phenocopy the response of primary cells in a label-free cell electrical impedance (CEI) sensing system that measures cell morphology and adhesion. We then investigated the signalling profile and membrane localisation of GPR84 upon treatment with 6-OAU and DL-175, two agonists known to differentially influence immune cell function. When compared to 6-OAU, DL-175 was found to exhibit a delayed impedance response, a delayed and suppressed activation of Akt, which together correlated with an impaired ability to internalise GPR84 from the plasma membrane. The signalling differences were transient and occurred only at early time points in the low expressing cell lines, highlighting the importance of receptor number and kinetic readouts when evaluating signalling bias. Our findings open new ways to understand GPR84 signalling and evaluate the effect of newly developed agonists.
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Affiliation(s)
- Vincent B Luscombe
- Sir William Dunn School of Pathology, South Parks Rd, University of Oxford, Oxford, Oxfordshire, OX1 3RE, United Kingdom
| | - Luis Alberto Baena-López
- Sir William Dunn School of Pathology, South Parks Rd, University of Oxford, Oxford, Oxfordshire, OX1 3RE, United Kingdom
| | - Carole J R Bataille
- Department of Chemistry, Mansfield Rd, University of Oxford, Oxford, Oxfordshire, OX1 3TA, United Kingdom
| | - Angela J Russell
- Department of Chemistry, Mansfield Rd, University of Oxford, Oxford, Oxfordshire, OX1 3TA, United Kingdom; Department of Pharmacology, Mansfield Rd, University of Oxford, Oxford, Oxfordshire, OX1 3TA, United Kingdom
| | - David R Greaves
- Sir William Dunn School of Pathology, South Parks Rd, University of Oxford, Oxford, Oxfordshire, OX1 3RE, United Kingdom.
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7
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Kouakou YI, Lee RJ. Interkingdom Detection of Bacterial Quorum-Sensing Molecules by Mammalian Taste Receptors. Microorganisms 2023; 11:1295. [PMID: 37317269 PMCID: PMC10221136 DOI: 10.3390/microorganisms11051295] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/11/2023] [Accepted: 05/13/2023] [Indexed: 06/16/2023] Open
Abstract
Bitter and sweet taste G protein-coupled receptors (known as T2Rs and T1Rs, respectively) were originally identified in type II taste cells on the tongue, where they signal perception of bitter and sweet tastes, respectively. Over the past ~15 years, taste receptors have been identified in cells all over the body, demonstrating a more general chemosensory role beyond taste. Bitter and sweet taste receptors regulate gut epithelial function, pancreatic β cell secretion, thyroid hormone secretion, adipocyte function, and many other processes. Emerging data from a variety of tissues suggest that taste receptors are also used by mammalian cells to "eavesdrop" on bacterial communications. These receptors are activated by several quorum-sensing molecules, including acyl-homoserine lactones and quinolones from Gram-negative bacteria such as Pseudomonas aeruginosa, competence stimulating peptides from Streptococcus mutans, and D-amino acids from Staphylococcus aureus. Taste receptors are an arm of immune surveillance similar to Toll-like receptors and other pattern recognition receptors. Because they are activated by quorum-sensing molecules, taste receptors report information about microbial population density based on the chemical composition of the extracellular environment. This review summarizes current knowledge of bacterial activation of taste receptors and identifies important questions remaining in this field.
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Affiliation(s)
- Yobouet Ines Kouakou
- Department of Otorhinolaryngology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Robert J. Lee
- Department of Otorhinolaryngology and Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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8
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Carey RM, Palmer JN, Adappa ND, Lee RJ. Loss of CFTR function is associated with reduced bitter taste receptor-stimulated nitric oxide innate immune responses in nasal epithelial cells and macrophages. Front Immunol 2023; 14:1096242. [PMID: 36742335 PMCID: PMC9890060 DOI: 10.3389/fimmu.2023.1096242] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/03/2023] [Indexed: 01/19/2023] Open
Abstract
Introduction Bitter taste receptors (T2Rs) are G protein-coupled receptors identified on the tongue but expressed all over the body, including in airway cilia and macrophages, where T2Rs serve an immune role. T2R isoforms detect bitter metabolites (quinolones and acyl-homoserine lactones) secreted by gram negative bacteria, including Pseudomonas aeruginosa, a major pathogen in cystic fibrosis (CF). T2R activation by bitter bacterial products triggers calcium-dependent nitric oxide (NO) production. In airway cells, the NO increases mucociliary clearance and has direct antibacterial properties. In macrophages, the same pathway enhances phagocytosis. Because prior studies linked CF with reduced NO, we hypothesized that CF cells may have reduced T2R/NO responses, possibly contributing to reduced innate immunity in CF. Methods Immunofluorescence, qPCR, and live cell imaging were used to measure T2R localization, calcium and NO signaling, ciliary beating, and antimicrobial responses in air-liquid interface cultures of primary human nasal epithelial cells and immortalized bronchial cell lines. Immunofluorescence and live cell imaging was used to measure T2R signaling and phagocytosis in primary human monocyte-derived macrophages. Results Primary nasal epithelial cells from both CF and non-CF patients exhibited similar T2R expression, localization, and calcium signals. However, CF cells exhibited reduced NO production also observed in immortalized CFBE41o- CF cells and non-CF 16HBE cells CRISPR modified with CF-causing mutations in the CF transmembrane conductance regulator (CFTR). NO was restored by VX-770/VX-809 corrector/potentiator pre-treatment, suggesting reduced NO in CF cells is due to loss of CFTR function. In nasal cells, reduced NO correlated with reduced ciliary and antibacterial responses. In primary human macrophages, inhibition of CFTR reduced NO production and phagocytosis during T2R stimulation. Conclusions Together, these data suggest an intrinsic deficiency in T2R/NO signaling caused by loss of CFTR function that may contribute to intrinsic susceptibilities of CF patients to P. aeruginosa and other gram-negative bacteria that activate T2Rs.
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Affiliation(s)
- Ryan M Carey
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - James N Palmer
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Nithin D Adappa
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Robert J Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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9
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Falà AK, Álvarez-Ordóñez A, Filloux A, Gahan CGM, Cotter PD. Quorum sensing in human gut and food microbiomes: Significance and potential for therapeutic targeting. Front Microbiol 2022; 13:1002185. [PMID: 36504831 PMCID: PMC9733432 DOI: 10.3389/fmicb.2022.1002185] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/17/2022] [Indexed: 11/27/2022] Open
Abstract
Human gut and food microbiomes interact during digestion. The outcome of these interactions influences the taxonomical composition and functional capacity of the resident human gut microbiome, with potential consequential impacts on health and disease. Microbe-microbe interactions between the resident and introduced microbiomes, which likely influence host colonisation, are orchestrated by environmental conditions, elements of the food matrix, host-associated factors as well as social cues from other microorganisms. Quorum sensing is one example of a social cue that allows bacterial communities to regulate genetic expression based on their respective population density and has emerged as an attractive target for therapeutic intervention. By interfering with bacterial quorum sensing, for instance, enzymatic degradation of signalling molecules (quorum quenching) or the application of quorum sensing inhibitory compounds, it may be possible to modulate the microbial composition of communities of interest without incurring negative effects associated with traditional antimicrobial approaches. In this review, we summarise and critically discuss the literature relating to quorum sensing from the perspective of the interactions between the food and human gut microbiome, providing a general overview of the current understanding of the prevalence and influence of quorum sensing in this context, and assessing the potential for therapeutic targeting of quorum sensing mechanisms.
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Affiliation(s)
- A. Kate Falà
- APC Microbiome Ireland, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland,Food Bioscience Department, Teagasc Food Research Centre, Fermoy, Ireland
| | - Avelino Álvarez-Ordóñez
- Department of Food Hygiene and Technology and Institute of Food Science and Technology, Universidad de León, León, Spain
| | - Alain Filloux
- MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Cormac G. M. Gahan
- APC Microbiome Ireland, University College Cork, Cork, Ireland,School of Microbiology, University College Cork, Cork, Ireland,School of Pharmacy, University College Cork, Cork, Ireland
| | - Paul D. Cotter
- APC Microbiome Ireland, University College Cork, Cork, Ireland,Food Bioscience Department, Teagasc Food Research Centre, Fermoy, Ireland,*Correspondence: Paul D. Cotter,
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Talmon M, Pollastro F, Fresu LG. The Complex Journey of the Calcium Regulation Downstream of TAS2R Activation. Cells 2022; 11:cells11223638. [PMID: 36429066 PMCID: PMC9688576 DOI: 10.3390/cells11223638] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/07/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022] Open
Abstract
Bitter taste receptors (TAS2Rs) have recently arisen as a potential drug target for asthma due to their localization in airway cells. These receptors are expressed in all cell types of the respiratory system comprising epithelial, smooth muscle and immune cells; however, the expression pattern of the subtypes is different in each cell type and, accordingly, so is their role, for example, anti-inflammatory or bronchodilator. The most challenging aspect in studying TAS2Rs has been the identification of the downstream signaling cascades. Indeed, TAS2R activation leads to canonical IP3-dependent calcium release from the ER, but, alongside, there are other mechanisms that differ according to the histological localization. In this review, we summarize the current knowledge on the cytosolic calcium modulation downstream of TAS2R activation in the epithelial, smooth muscle and immune cells of the airway system.
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Affiliation(s)
- Maria Talmon
- Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
- Correspondence: (M.T.); (L.G.F.); Tel.: +39-0321-660589 (M.T.); +39-0321-660687 (L.G.F.)
| | - Federica Pollastro
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2/3, 28100 Novara, Italy
| | - Luigia Grazia Fresu
- Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
- Correspondence: (M.T.); (L.G.F.); Tel.: +39-0321-660589 (M.T.); +39-0321-660687 (L.G.F.)
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Abstract
Taste receptors are receptor proteins that detect ligands belonging to the 5 taste modalities: sweet, bitter, sour, salty, and umami. Taste receptors are not restricted to taste cells in taste buds; rather, they are distributed throughout the entire body. For example, solitary chemosensory cells (SCCs) and tuft cells express taste signal proteins and are present in several mucosae. In the airways, SCCs sense bacteria, allergens, viruses, and noxious stimuli and drive evasive behavior, neuroinflammation, and antibacterial responses. In the gut, tuft cells detect helminth infection and bacterial dysbiosis and initiate type II immune responses characterized by tissue remodeling. In the gingiva, SCCs detect oral pathogenic bacteria, evoke innate immune responses and release antimicrobial compounds in the epithelium, and regulate the microbiome composition. This review summarizes the most recent research on extragustatory taste receptors and their function in antibacterial defense. We also discuss how these findings have provided insights into the development of potential therapeutic strategies for mucosal bacterial infection and dental diseases.
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Affiliation(s)
- R. Xi
- Department of Cariology and Endodontics, Sichuan University, West China Hospital of Stomatology, Chengdu, China
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - X. Zheng
- Department of Cariology and Endodontics, Sichuan University, West China Hospital of Stomatology, Chengdu, China
| | - M. Tizzano
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Khimsuksri S, Paphangkorakit J, Pitiphat W, Coldwell SE. TAS2R38 polymorphisms and oral diseases in Thais: a cross-sectional study. BMC Oral Health 2022; 22:21. [PMID: 35090440 PMCID: PMC8796631 DOI: 10.1186/s12903-022-02043-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/30/2021] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Polymorphisms at positions 49, 262, and 296 in the TAS2R38 bitter taste receptor gene result in two common genetic haplotypes, PAV and AVI, named for the resulting amino acid substitutions. TAS2R38 genotype has been previously associated with caries risk in children. This study aimed to identify TAS2R38 polymorphisms among Thais and to explore any association between genotype and oral diseases.
Methods
Patients seeking care at Khon Kaen University Dental Hospital in Thailand were recruited to participate in the study. Saliva was collected for DNA extraction and genotyping. Patients completed a questionnaire to collect demographic variables and assess oral self-care behaviors. A calibrated dentist conducted an examination that included periodontal charting and recording of decayed, missing, and filled teeth (DMFT).
Results
A total of 250 patients (19–75 years) were enrolled in the study (116 males). Two haplotypes, PAV (67.2%) and AVI (32.8%) were found, resulting in 3 diplotypes; PAV/PAV (46.0%), PAV/AVI (42.4%) and AVI/AVI (11.6%). DMFT and periodontal status of 238 participants were recorded. The three diplotype groups were similar in age, sex, socio-economic indicators, oral self-care, and number of teeth. The odds of having periodontal disease, defined as at least one site with probing depth ≥ 5 mm, were lower in AVI/AVI and PAV/AVI compared with PAV/PAV. PAV/AVI tended to have less DMFT, while AVI/AVI tended to have more DMFT compared with PAV/PAV, however these trends did not reach statistical significance.
Conclusions
The frequency distribution of TAS2R38 genotypes was similar to that reported for other Asian populations. AVI/AVI genotype was associated with decreased prevalence of periodontal disease among Thai dental patients, whereas there was no significant association between TAS2R38 genotype and prevalence of tooth decay in this patient population.
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Fan Q, Wang H, Mao C, Li J, Zhang X, Grenier D, Yi L, Wang Y. Structure and Signal Regulation Mechanism of Interspecies and Interkingdom Quorum Sensing System Receptors. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:429-445. [PMID: 34989570 DOI: 10.1021/acs.jafc.1c04751] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Quorum sensing (QS) is a signaling mechanism for cell-to-cell communication between bacteria, fungi, and even eukaryotic hosts such as plant and animal cells. Bacteria in real life do not exist as isolated organisms but are found in complex, dynamic, and microecological environments. The study of interspecies QS and interkingdom QS is a valuable approach for exploring bacteria-bacteria interactions and bacteria-host interaction mechanisms and has received considerable attention from researchers. The correct combination of QS signals and receptors is key to initiating the QS process. Compared with intraspecies QS, the signal regulation mechanism of interspecies QS and interkingdom QS is often more complicated, and the distribution of receptors is relatively wide. The present review focuses on the latest progress with respect to the distribution, structure, and signal transduction of interspecies and interkingdom QS receptors and provides a guide for the investigation of new QS receptors in the future.
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Affiliation(s)
- Qingying Fan
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
- Key Laboratory of Molecular Pathogen and Immunology of Animal of Luoyang, Luoyang 471000, China
| | - Haikun Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
- Key Laboratory of Molecular Pathogen and Immunology of Animal of Luoyang, Luoyang 471000, China
| | - Chenlong Mao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
- Key Laboratory of Molecular Pathogen and Immunology of Animal of Luoyang, Luoyang 471000, China
| | - Jinpeng Li
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
- Key Laboratory of Molecular Pathogen and Immunology of Animal of Luoyang, Luoyang 471000, China
| | - Xiaoling Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
- Key Laboratory of Molecular Pathogen and Immunology of Animal of Luoyang, Luoyang 471000, China
| | - Daniel Grenier
- Groupe de Recherche en Écologie Buccale (GREB), Faculté de Médecine Dentaire, Université Laval, Quebec City, Quebec G1 V 0A6, Canada
| | - Li Yi
- College of Life Science, Luoyang Normal University, Luoyang 471023, China
| | - Yang Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
- Key Laboratory of Molecular Pathogen and Immunology of Animal of Luoyang, Luoyang 471000, China
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Tiroch J, Sterneder S, Di Pizio A, Lieder B, Hoelz K, Holik AK, Pignitter M, Behrens M, Somoza M, Ley JP, Somoza V. Bitter Sensing TAS2R50 Mediates the trans-Resveratrol-Induced Anti-inflammatory Effect on Interleukin 6 Release in HGF-1 Cells in Culture. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:13339-13349. [PMID: 33461297 DOI: 10.1021/acs.jafc.0c07058] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Recent data have shown anti-inflammatory effects for trans-resveratrol (RSV) and rosmarinic acid (RA) in various immune-competent cell models through reduction of lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release. Because both compounds have been reported to taste bitter, we hypothesized an involvement of human bitter taste sensing receptors (TAS2Rs) on IL-6 release in LPS-treated human gingival fibroblasts (HGF-1). First, the bitter taste intensity of RSV and RA was compared in a sensory trial with 10 untrained panelists, of whom 90% rated a 50 ppm of RSV in water solution more bitter than 50 ppm of RA. A mean 19 ± 6% reduction of the RSV-induced bitter taste intensity was achieved by co-administration of 50 ppm of the bitter-masking, TAS2R43 antagonist homoeriodictyol (HED). Mechanistic experiments in a stably CRISPR-Cas9-edited TAS2R43ko gastric cell model revealed involvement of TAS2R43 in the HED-evoked effect on RSV-induced proton secretion, whereas the cellular response to RSV did not depend upon TAS2R43. Next, the IL-6 modulatory effect of 100 μM RSV was studied in LPS-treated immune-competent HGF-1 cells. After 6 h of treatment, RSV reduced the LPS-induced IL-6 gene expression and protein release by -46.2 ± 12.7 and -73.9 ± 2.99%, respectively. This RSV-evoked effect was abolished by co-administration of HED. Because real-time quantitative polymerase chain reaction analyses revealed a regulation of TAS2R50 in RSV with or without HED-treated HGF-1 cells, an siRNA knockdown approach of TAS2R50 was applied to verify TAS2R50 involvement in the RSV-induced reduction of the LPS-evoked IL-6 release in HGT-1 cells.
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Affiliation(s)
- Johanna Tiroch
- Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Sonja Sterneder
- Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Antonella Di Pizio
- Leibniz-Institute of Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany
| | - Barbara Lieder
- Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Kathrin Hoelz
- Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Ann-Katrin Holik
- Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Marc Pignitter
- Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Maik Behrens
- Leibniz-Institute of Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany
| | - Mark Somoza
- Leibniz-Institute of Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany
- Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354 Freising, Germany
| | | | - Veronika Somoza
- Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
- Leibniz-Institute of Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany
- Chair for Nutritional Systems Biology, Technical University of Munich, 85354 Freising, Germany
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15
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Coquant G, Aguanno D, Pham S, Grellier N, Thenet S, Carrière V, Grill JP, Seksik P. Gossip in the gut: Quorum sensing, a new player in the host-microbiota interactions. World J Gastroenterol 2021; 27:7247-7270. [PMID: 34876787 PMCID: PMC8611211 DOI: 10.3748/wjg.v27.i42.7247] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/17/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Bacteria are known to communicate with each other and regulate their activities in social networks by secreting and sensing signaling molecules called autoinducers, a process known as quorum sensing (QS). This is a growing area of research in which we are expanding our understanding of how bacteria collectively modify their behavior but are also involved in the crosstalk between the host and gut microbiome. This is particularly relevant in the case of pathologies associated with dysbiosis or disorders of the intestinal ecosystem. This review will examine the different QS systems and the evidence for their presence in the intestinal ecosystem. We will also provide clues on the role of QS molecules that may exert, directly or indirectly through their bacterial gossip, an influence on intestinal epithelial barrier function, intestinal inflammation, and intestinal carcinogenesis. This review aims to provide evidence on the role of QS molecules in gut physiology and the potential shared by this new player. Better understanding the impact of intestinal bacterial social networks and ultimately developing new therapeutic strategies to control intestinal disorders remains a challenge that needs to be addressed in the future.
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Affiliation(s)
- Garance Coquant
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Doriane Aguanno
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- EPHE, PSL University, Paris 75014, France
| | - Sandrine Pham
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- EPHE, PSL University, Paris 75014, France
| | - Nathan Grellier
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Sophie Thenet
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- EPHE, PSL University, Paris 75014, France
| | - Véronique Carrière
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Jean-Pierre Grill
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
| | - Philippe Seksik
- Centre de Recherche Saint-Antoine, INSERM, Sorbonne Université, Paris 75012, France
- Department of Gastroenterology and Nutrition, Saint-Antoine Hospital, APHP, Paris 75012, France
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16
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Martens K, Steelant B, Bullens DMA. Taste Receptors: The Gatekeepers of the Airway Epithelium. Cells 2021; 10:cells10112889. [PMID: 34831117 PMCID: PMC8616034 DOI: 10.3390/cells10112889] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/17/2021] [Accepted: 10/22/2021] [Indexed: 02/07/2023] Open
Abstract
Taste receptors are well known for their role in the sensation of taste. Surprisingly, the expression and involvement of taste receptors in chemosensory processes outside the tongue have been recently identified in many organs including the airways. Currently, a clear understanding of the airway-specific function of these receptors and the endogenous activating/inhibitory ligands is lagging. The focus of this review is on recent physiological and clinical data describing the taste receptors in the airways and their activation by secreted bacterial compounds. Taste receptors in the airways are potentially involved in three different immune pathways (i.e., the production of nitric oxide and antimicrobial peptides secretion, modulation of ciliary beat frequency, and bronchial smooth muscle cell relaxation). Moreover, genetic polymorphisms in these receptors may alter the patients’ susceptibility to certain types of respiratory infections as well as to differential outcomes in patients with chronic inflammatory airway diseases such as chronic rhinosinusitis and asthma. A better understanding of the function of taste receptors in the airways may lead to the development of a novel class of therapeutic molecules that can stimulate airway mucosal immune responses and could treat patients with chronic airway diseases.
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Affiliation(s)
- Katleen Martens
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium; (K.M.); (B.S.)
- Department of Bioscience Engineering, University of Antwerp, 2020 Antwerp, Belgium
| | - Brecht Steelant
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium; (K.M.); (B.S.)
| | - Dominique M. A. Bullens
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium; (K.M.); (B.S.)
- Clinical Division of Pediatrics, University Hospitals Leuven, 3000 Leuven, Belgium
- Correspondence:
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17
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Abstract
Bitter taste-sensing type 2 receptors (TAS2Rs or T2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), are of crucial importance in the perception of bitterness. Although in the first instance, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, numerous studies have detected these sensory receptor proteins in several extra-oral tissues, such as in pancreatic or ovarian tissues, as well as in their corresponding malignancies. Critical points of extra-oral TAS2Rs biology, such as their structure, roles, signaling transduction pathways, extensive mutational polymorphism, and molecular evolution, have been currently broadly studied. The TAS2R cascade, for instance, has been recently considered to be a pivotal modulator of a number of (patho)physiological processes, including adipogenesis or carcinogenesis. The latest advances in taste receptor biology further raise the possibility of utilizing TAS2Rs as a therapeutic target or as an informative index to predict treatment responses in various disorders. Thus, the focus of this review is to provide an update on the expression and molecular basis of TAS2Rs functions in distinct extra-oral tissues in health and disease. We shall also discuss the therapeutic potential of novel TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles.
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Affiliation(s)
- Kamila Tuzim
- Department of Clinical Pathomorphology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090, Lublin, Poland.
| | - Agnieszka Korolczuk
- Department of Clinical Pathomorphology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090, Lublin, Poland
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18
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Neuropeptide Y Reduces Nasal Epithelial T2R Bitter Taste Receptor-Stimulated Nitric Oxide Production. Nutrients 2021; 13:nu13103392. [PMID: 34684394 PMCID: PMC8538228 DOI: 10.3390/nu13103392] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 12/30/2022] Open
Abstract
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.
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Medapati MR, Bhagirath AY, Singh N, Schroth RJ, Bhullar RP, Duan K, Chelikani P. Bitter Taste Receptor T2R14 Modulates Gram-Positive Bacterial Internalization and Survival in Gingival Epithelial Cells. Int J Mol Sci 2021; 22:ijms22189920. [PMID: 34576085 PMCID: PMC8469602 DOI: 10.3390/ijms22189920] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/10/2021] [Accepted: 09/11/2021] [Indexed: 01/01/2023] Open
Abstract
Bitter-taste receptors (T2Rs) have emerged as key players in host–pathogen interactions and important modulators of oral innate immunity. Previously, we reported that T2R14 is expressed in gingival epithelial cells (GECs) and interacts with competence stimulating peptides (CSPs) secreted by the cariogenic Streptococcus mutans. The underlying mechanisms of the innate immune responses and physiological effects of T2R14 on Gram-positive bacteria are not well characterized. In this study, we examined the role of T2R14 in internalization and growth inhibitory effects on Gram-positive bacteria, namely Staphylococcus aureus and S. mutans. We utilized CRISPR-Cas9 T2R14 knockdown (KD) GECs as the study model to address these key physiological mechanisms. Our data reveal that the internalization of S. aureus is significantly decreased, while the internalization of S. mutans remains unaffected upon knockdown of T2R14 in GECs. Surprisingly, GECs primed with S. mutans CSP-1 resulted in an inhibition of growth for S. aureus, but not for S. mutans. The GECs infected with S. aureus induced T2R14-dependent human β-defensin-2 (hBD-2) secretion; however, S. mutans–infected GECs did not induce hBD-2 secretion, but induced T2R14 dependent IL-8 secretion. Interestingly, our results show that T2R14 KD affects the cytoskeletal reorganization in GECs, thereby inhibiting S. aureus internalization. Our study highlights the distinct mechanisms and a direct role of T2R14 in influencing physiological responses to Gram-positive bacteria in the oral cavity.
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Affiliation(s)
- Manoj Reddy Medapati
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada; (M.R.M.); (A.Y.B.); (N.S.); (R.J.S.); (R.P.B.); (K.D.)
| | - Anjali Yadav Bhagirath
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada; (M.R.M.); (A.Y.B.); (N.S.); (R.J.S.); (R.P.B.); (K.D.)
- Children’s Hospital Research Institute of Manitoba (CHRIM), University of Manitoba, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada
| | - Nisha Singh
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada; (M.R.M.); (A.Y.B.); (N.S.); (R.J.S.); (R.P.B.); (K.D.)
| | - Robert J. Schroth
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada; (M.R.M.); (A.Y.B.); (N.S.); (R.J.S.); (R.P.B.); (K.D.)
- Children’s Hospital Research Institute of Manitoba (CHRIM), University of Manitoba, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada
- Department of Preventive Dental Sciences, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada
| | - Rajinder P. Bhullar
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada; (M.R.M.); (A.Y.B.); (N.S.); (R.J.S.); (R.P.B.); (K.D.)
| | - Kangmin Duan
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada; (M.R.M.); (A.Y.B.); (N.S.); (R.J.S.); (R.P.B.); (K.D.)
- Children’s Hospital Research Institute of Manitoba (CHRIM), University of Manitoba, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada
| | - Prashen Chelikani
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Rady Faculty of Health Sciences, Dr. Gerald Niznick College of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, MB R3E 0W2, Canada; (M.R.M.); (A.Y.B.); (N.S.); (R.J.S.); (R.P.B.); (K.D.)
- Children’s Hospital Research Institute of Manitoba (CHRIM), University of Manitoba, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada
- Correspondence: ; Tel.: +1-204-789-3539; Fax: +1-204-789-3913
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20
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Dhanaraj P, Muthiah I, Rozbu MR, Nuzhat S, Paulraj MS. Computational Studies on T2Rs Agonist-Based Anti-COVID-19 Drug Design. Front Mol Biosci 2021; 8:637124. [PMID: 34485378 PMCID: PMC8416165 DOI: 10.3389/fmolb.2021.637124] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 07/02/2021] [Indexed: 11/13/2022] Open
Abstract
The expeditious and world pandemic viral disease of new coronavirus (SARS-CoV-2) has formed a prompt urgency to discover auspicious target-based ligand for the treatment of COVID-19. Symptoms of novel coronavirus disease (COVID-19) typically include dry cough, fever, and shortness of breath. Recent studies on many COVID-19 patients in Italy and the United Kingdom found increasing anosmia and ageusia among the COVID-19-infected patients. SARS-CoV-2 possibly infects neurons in the nasal passage and disrupts the senses of smell and taste, like other coronaviruses, such as SARS-CoV and MERS-CoV that could target the central nervous system. Developing a drug based on the T2Rs might be of better understanding and worth finding better molecules to act against COVID-19. In this research, we have taken a taste receptor agonist molecule to find a better core molecule that may act as the best resource to design a drug or corresponding derivatives. Based on the computational docking studies, the antibiotic tobramycin showed the best interaction against 6LU7 COVID-19 main protease. Aromatic carbonyl functional groups of the molecule established intermolecular hydrogen bonding interaction with GLN189 amino acid and it showed the two strongest carbonyl interactions with receptor protein resulting in a glide score of -11.159. To conclude, depending on the molecular recognition of the GPCR proteins, the agonist molecule can be recognized to represent the cell secondary mechanism; thus, it provides enough confidence to design a suitable molecule based on the tobramycin drug.
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Affiliation(s)
- Premnath Dhanaraj
- Department of Biotechnology, School of Agriculture and Biosciences, Karunya Institute of Technology and Science (Deemed to be University), Coimbatore, India
| | - Indiraleka Muthiah
- Department of Biotechnology, Mepco Schlenk Engineering College, Sivakasi, India
| | - Mahtabin Rodela Rozbu
- Department of Science and Math Program, Asian University for Women, Chittagong, Bangladesh
| | - Samiha Nuzhat
- Department of Science and Math Program, Asian University for Women, Chittagong, Bangladesh
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21
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Krasulova K, Illes P. Intestinal interplay of quorum sensing molecules and human receptors. Biochimie 2021; 189:108-119. [PMID: 34186126 DOI: 10.1016/j.biochi.2021.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/03/2021] [Accepted: 06/22/2021] [Indexed: 12/20/2022]
Abstract
Human gut is in permanent contact with microorganisms that play an important role in many physiological processes including metabolism and immunologic activity. These microorganisms communicate and manage themself by the quorum sensing system (QS) that helps to coordinate optimal growth and subsistence by activating signaling pathways that regulate bacterial gene expression. Diverse QS molecules produced by pathogenic as well as resident microbiota have been found throughout the human gut. However, even a host can by affected by these molecules. Intestinal and immune cells possess a range of molecular targets for QS. Our present knowledge on bacteria-cell communication encompasses G-protein-coupled receptors, nuclear receptors and receptors for bacterial cell-wall components. The QS of commensal bacteria has been approved as a protective factor with favourable effects on intestinal homeostasis and immunity. Signaling molecules of QS interacting with above-mentioned receptors thus parcipitate on maintaining of barrier functions, control of inflammation processes and increase of resistance to pathogen colonization in host organisms. Pathogens QS molecules can have a dual function. Host cells are able to detect the ongoing infection by monitoring the presence and changes in concentrations of QS molecules. Such information can help to set the most effective immune defence to prevent or overcome the infection. Contrary, pathogens QS signals can target the host receptors to deceive the immune system to get the best conditions for growth. However, our knowledge about communication mediated by QS is still limited and detailed understanding of molecular mechanisms of QS signaling is desired.
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Affiliation(s)
- Kristyna Krasulova
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
| | - Peter Illes
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic
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22
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Pu Q, Guo K, Lin P, Wang Z, Qin S, Gao P, Combs C, Khan N, Xia Z, Wu M. Bitter receptor TAS2R138 facilitates lipid droplet degradation in neutrophils during Pseudomonas aeruginosa infection. Signal Transduct Target Ther 2021; 6:210. [PMID: 34083514 PMCID: PMC8175399 DOI: 10.1038/s41392-021-00602-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 03/04/2021] [Accepted: 04/01/2021] [Indexed: 02/05/2023] Open
Abstract
Bitter receptors function primarily in sensing taste, but may also have other functions, such as detecting pathogenic organisms due to their agile response to foreign objects. The mouse taste receptor type-2 member 138 (TAS2R138) is a member of the G-protein-coupled bitter receptor family, which is not only found in the tongue and nasal cavity, but also widely distributed in other organs, such as the respiratory tract, gut, and lungs. Despite its diverse functions, the role of TAS2R138 in host defense against bacterial infection is largely unknown. Here, we show that TAS2R138 facilitates the degradation of lipid droplets (LDs) in neutrophils during Pseudomonas aeruginosa infection through competitive binding with PPARG (peroxisome proliferator-activated receptor gamma) antagonist: N-(3-oxododecanoyl)-L-homoserine lactone (AHL-12), which coincidently is a virulence-bound signal produced by this bacterium (P. aeruginosa). The released PPARG then migrates from nuclei to the cytoplasm to accelerate the degradation of LDs by binding PLIN2 (perilipin-2). Subsequently, the TAS2R138-AHL-12 complex targets LDs to augment their degradation, and thereby facilitating the clearance of AHL-12 in neutrophils to maintain homeostasis in the local environment. These findings reveal a crucial role for TAS2R138 in neutrophil-mediated host immunity against P. aeruginosa infection.
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Affiliation(s)
- Qinqin Pu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA
| | - Kai Guo
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA
| | - Ping Lin
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA
- Wound Trauma Medical Center, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
- Biological Science Research Center, Southwest University, Chongqing, 400716, China
| | - Zhihan Wang
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Shugang Qin
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China
| | - Pan Gao
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA
| | - Colin Combs
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA
| | - Nadeem Khan
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA.
| | - Zhenwei Xia
- Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Min Wu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA.
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Tran HTT, Stetter R, Herz C, Spöttel J, Krell M, Hanschen FS, Schreiner M, Rohn S, Behrens M, Lamy E. Allyl Isothiocyanate: A TAS2R38 Receptor-Dependent Immune Modulator at the Interface Between Personalized Medicine and Nutrition. Front Immunol 2021; 12:669005. [PMID: 33968075 PMCID: PMC8103899 DOI: 10.3389/fimmu.2021.669005] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/29/2021] [Indexed: 11/13/2022] Open
Abstract
Understanding individual responses to nutrition and medicine is of growing interest and importance. There is evidence that differences in bitter taste receptor (TAS2R) genes which give rise to two frequent haplotypes, TAS2R38-PAV (functional) and TAS2R38-AVI (non-functional), may impact inter-individual differences in health status. We here analyzed the relevance of the TAS2R38 receptor in the regulation of the human immune response using the TAS2R38 agonist allyl isothiocyanate (AITC) from Brassica plants. A differential response in calcium mobilization upon AITC treatment in leucocytes from healthy humans confirmed a relevance of TAS2R38 functionality, independent from cation channel TRPV1 or TRPA1 activation. We further identified a TAS2R38-dependence of MAPK and AKT signaling activity, bactericidal (toxicity against E. coli) and anti-inflammatory activity (TNF-alpha inhibition upon cell stimulation). These in vitro results were derived at relevant human plasma levels in the low micro molar range as shown here in a human intervention trial with AITC-containing food.
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Affiliation(s)
- Hoai T T Tran
- Molecular Preventive Medicine, University Medical Center and Faculty of Medicine-University of Freiburg, Freiburg, Germany
| | - Rebecca Stetter
- Molecular Preventive Medicine, University Medical Center and Faculty of Medicine-University of Freiburg, Freiburg, Germany
| | - Corinna Herz
- Molecular Preventive Medicine, University Medical Center and Faculty of Medicine-University of Freiburg, Freiburg, Germany
| | - Jenny Spöttel
- Institute of Food Technology and Food Chemistry, Technical University of Berlin, Berlin, Germany
| | - Mareike Krell
- Institute of Food Technology and Food Chemistry, Technical University of Berlin, Berlin, Germany
| | - Franziska S Hanschen
- Plant Quality and Food Security, Leibniz Institute of Vegetable and Ornamental Crops, Großbeeren, Germany
| | - Monika Schreiner
- Plant Quality and Food Security, Leibniz Institute of Vegetable and Ornamental Crops, Großbeeren, Germany
| | - Sascha Rohn
- Institute of Food Technology and Food Chemistry, Technical University of Berlin, Berlin, Germany
| | - Maik Behrens
- Section II: Metabolic Function, Chemoreception & Biosignals, Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany
| | - Evelyn Lamy
- Molecular Preventive Medicine, University Medical Center and Faculty of Medicine-University of Freiburg, Freiburg, Germany
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24
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Cheng W, Yao M, Liu F. Bitter Taste Receptor as a Therapeutic Target in Orthopaedic Disorders. Drug Des Devel Ther 2021; 15:895-903. [PMID: 33679130 PMCID: PMC7926036 DOI: 10.2147/dddt.s289614] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 02/10/2021] [Indexed: 12/11/2022] Open
Abstract
Non-gustatory, extraoral bitter taste receptors (T2Rs) are G-protein coupled receptors that are expressed throughout the body and have various functional responses when stimulated by bitter agonists. Presently, T2Rs have been found to be expressed in osteoclasts and osteocytes where osteoclasts were capable of detecting bacterial quorum-sensing molecules through the T2R38 isoform. In the innate immune system, stimulating T2Rs induces anti-inflammatory and anti-pathogenic effects through the phospholipase C/inositol triphosphate pathway, which leads to intracellular calcium release from the endoplasmic reticulum. The immune cells with functional responses to T2R activation also play a role in bone inflammation and orthopaedic disorders. Furthermore, increasing intracellular calcium levels in bone cells through T2R activation can potentially influence bone formation and resorption. With recent studies finding T2R expression in bone cells, we examine the potential of targeting this receptor to treat bone inflammation and to promote bone anabolism.
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Affiliation(s)
- Weyland Cheng
- Department of Orthopaedic Surgery, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China
- Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China
| | - Manye Yao
- Department of Orthopaedic Surgery, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China
| | - Fangna Liu
- Department of Orthopaedic Surgery, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, Henan, People’s Republic of China
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25
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Sell EA, Ortiz-Carpena JF, Herbert DR, Cohen NA. Tuft cells in the pathogenesis of chronic rhinosinusitis with nasal polyps and asthma. Ann Allergy Asthma Immunol 2021; 126:143-151. [PMID: 33122124 PMCID: PMC8674819 DOI: 10.1016/j.anai.2020.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 10/10/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To review the latest discoveries regarding the role of tuft cells in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis and asthma. DATA SOURCES Reviews and primary research manuscripts were identified from PubMed, Google, and bioRxiv using the search words airway epithelium, nasal polyposis, CRS or asthma and chemoreceptor cell, solitary chemosensory cell, brush cell, microvillus cell, and tuft cell. STUDY SELECTIONS Studies were selected on the basis of novelty and likely relevance to the functions of tuft cells in chronic inflammatory diseases in the upper and lower airways. RESULTS Tuft cells coordinate a variety of immune responses throughout the body. After the activation of bitter-taste receptors, tuft cells coordinate the secretion of antimicrobial products by adjacent epithelial cells and initiate the calcium-dependent release of acetylcholine resulting in neurogenic inflammation, including mast cell degranulation and plasma extravasation. Tuft cells are also the dominant source of interleukin-25 and a significant source of cysteinyl leukotrienes that play a role in initiating inflammatory processes in the airway. Tuft cells have also been found to seem de novo in the distal airway after a viral infection, implicating these cells in dysplastic remodeling in the distal lung in the pathogenesis of asthma. CONCLUSION Tuft cells bridge innate and adaptive immunes responses and play an upstream role in initiating type 2 inflammation in the upper and possibly the lower airway. The role of tuft cells in respiratory pathophysiology must be further investigated, because tuft cells are putative high-value therapeutic targets for novel therapeutics in CRS with nasal polyps and asthma.
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Affiliation(s)
- Elizabeth A Sell
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Jorge F Ortiz-Carpena
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
| | - De'Broski R Herbert
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
| | - Noam A Cohen
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Rhinology, Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Corporal Michael J. Crescenz Veterans Administration Medical Center, Veterans Health Administration, United States Department of Veteran Affairs, Philadelphia, Pennsylvania; Monell Chemical Senses Center, Philadelphia, Pennsylvania
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26
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Medapati MR, Bhagirath AY, Singh N, Chelikani P. Pharmacology of T2R Mediated Host-Microbe Interactions. Handb Exp Pharmacol 2021; 275:177-202. [PMID: 33580389 DOI: 10.1007/164_2021_435] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bitter taste receptors (T2Rs) belong to the G protein-coupled receptor superfamily. Humans express 25 T2Rs that are known to detect several bitter compounds including bacterial quorum sensing molecules (QSM). Primarily found to be key receptors for bitter sensation T2Rs are known to play an important role in mediating innate immune responses in oral and extraoral tissues. Several studies have led to identification of Gram-negative and Gram-positive bacterial QSMs as agonists for T2Rs in airway epithelial cells and immune cells. However, the pharmacological characterization for many of the QSM-T2R interactions remains poorly defined. In this chapter, we discuss the extraoral roles including localization of T2Rs in extracellular vesicles, molecular pharmacology of QSM-T2R interactions, role of T2Rs in mediating innate immune responses, and some of the challenges in understanding T2R pharmacology.
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Affiliation(s)
- Manoj Reddy Medapati
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Dr. Gerald Niznick College of Dentistry, University of Manitoba, Winnipeg, MB, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
| | - Anjali Y Bhagirath
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Dr. Gerald Niznick College of Dentistry, University of Manitoba, Winnipeg, MB, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
| | - Nisha Singh
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Dr. Gerald Niznick College of Dentistry, University of Manitoba, Winnipeg, MB, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
| | - Prashen Chelikani
- Manitoba Chemosensory Biology Research Group, Department of Oral Biology, Dr. Gerald Niznick College of Dentistry, University of Manitoba, Winnipeg, MB, Canada.
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
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27
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Dapunt U, Prior B, Kretzer JP, Giese T, Zhao Y. Bacterial Biofilm Components Induce an Enhanced Inflammatory Response Against Metal Wear Particles. Ther Clin Risk Manag 2020; 16:1203-1212. [PMID: 33324065 PMCID: PMC7733385 DOI: 10.2147/tcrm.s280042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/18/2020] [Indexed: 11/25/2022] Open
Abstract
Purpose Aseptic implant loosening is still a feared complication in the field of orthopaedics. Presumably, a chronic inflammatory response is induced by wear particles, which leads to osteoclast generation, bone degradation and hence loosening of the implant. Since it has been demonstrated in the literature that most implants are in fact colonized by bacteria, the question arises whether aseptic implant loosening is truly aseptic. The aim of this study was to investigate a possibly enhanced inflammatory response to metal wear particles in the context of subclinical infection. Patients and Methods Tissue samples were collected intra-operatively from patients undergoing implant-exchange surgery due to aseptic loosening. Histopathological analysis was performed, as well as gene expression analysis for the pro-inflammatory cytokine Interleukin-8. By a series of in vitro experiments, the effect of metal wear particles on human monocytes, polymorphonuclear neutrophiles and osteoblasts was investigated. Additionally, minor amounts of lipoteichoic acid (LTA) and the bacterial heat shock protein GroEL were added. Results Histopathology of tissue samples revealed an accumulation of metal wear particles, as well as a cellular infiltrate consisting predominately of mononuclear cells. Furthermore, high expression of IL-8 could be detected in tissue surrounding the implant. Monocytes and osteoblasts in particular showed an increased release of IL-8 after stimulation with metal wear particles and in particular after stimulation with bacterial components and wear particles together. Conclusion We were able to show that minor amounts of bacterial components and metal wear particles together induce an enhanced inflammatory response in human monocytes and osteoblasts. This effect could significantly contribute to the generation of bone-resorbing osteoclasts and hence implant-loosening.
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Affiliation(s)
- Ulrike Dapunt
- Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg 69118, Germany
| | - Birgit Prior
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg 69120, Germany
| | - Jan Philippe Kretzer
- Laboratory of Biomechanics and Implant Research, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg 69118, Germany
| | - Thomas Giese
- Institute for Immunology, Heidelberg University, Heidelberg 69120, Germany
| | - Yina Zhao
- Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg 69118, Germany
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28
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Shrestha A, Schikora A. AHL-priming for enhanced resistance as a tool in sustainable agriculture. FEMS Microbiol Ecol 2020; 96:5957528. [DOI: 10.1093/femsec/fiaa226] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/04/2020] [Indexed: 01/28/2023] Open
Abstract
ABSTRACTBacteria communicate with each other through quorum sensing (QS) molecules. N-acyl homoserine lactones (AHL) are one of the most extensively studied groups of QS molecules. The role of AHL molecules is not limited to interactions between bacteria; they also mediate inter-kingdom interaction with eukaryotes. The perception mechanism of AHL is well-known in bacteria and several proteins have been proposed as putative receptors in mammalian cells. However, not much is known about the perception of AHL in plants. Plants generally respond to short-chained AHL with modification in growth, while long-chained AHL induce AHL-priming for enhanced resistance. Since plants may host several AHL-producing bacteria and encounter multiple AHL at once, a coordinated response is required. The effect of the AHL combination showed relatively low impact on growth but enhanced resistance. Microbial consortium of bacterial strains that produce different AHL could therefore be an interesting approach in sustainable agriculture. Here, we review the molecular and genetical basis required for AHL perception. We highlight recent advances in the field of AHL-priming. We also discuss the recent discoveries on the impact of combination(s) of multiple AHL on crop plants and the possible use of this knowledge in sustainable agriculture.
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Affiliation(s)
- Abhishek Shrestha
- Julius Kühn Institute (JKI) - Federal Research Centre for Cultivated Plants, Institute for Epidemiology and Pathogen Diagnostics, Messeweg 11/12, 38104 Braunschweig, Germany
| | - Adam Schikora
- Julius Kühn Institute (JKI) - Federal Research Centre for Cultivated Plants, Institute for Epidemiology and Pathogen Diagnostics, Messeweg 11/12, 38104 Braunschweig, Germany
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29
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Dapunt U, Prior B, Oelkrug C, Kretzer JP. IgY Targeting Bacterial Quorum-Sensing Molecules in Implant-Associated Infections. Molecules 2020; 25:molecules25174027. [PMID: 32899313 PMCID: PMC7504788 DOI: 10.3390/molecules25174027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 09/01/2020] [Indexed: 12/27/2022] Open
Abstract
Background: Implant-associated infections are still a major complication in the field of orthopedics. Bacteria can form biofilms on implant surfaces, making them more difficult to detect and treat. Since standard antibiotic therapy is often impaired in biofilm infections, particular interest is directed towards finding treatment alternatives. Biofilm-formation is a well-organized process during which bacteria communicate via quorum-sensing molecules (QSM). The aim of this study was to inhibit bacterial communication by directing avian IgY against specific QSM. Methods: Chicken were immunized against the following QSM: (1) AtlE, a member of the autolysin family which mediates attachment to a surface in Staphylococcus epidermidis; (2) GroEL, the bacterial heat shock protein; (3) PIA (polysaccharide intercellular adhesion), which is essential for cell–cell adhesion in biofilms. Staphylococcus epidermidis biofilms were grown and inhibition of biofilm-formation by IgYs was evaluated. Additionally, human osteoblasts were cultivated and biocompatibility of IgYs was tested. Results: We were able to demonstrate that all IgYs reduced biofilm-formation, also without prior immunization. Therefore, the response was probably not specific with regard to the QSM. Osteoblasts were activated by all IgYs which was demonstrated by microscopy and an increased release of IL-8. Conclusions: In conclusion, avian IgY inhibits biofilm-formation, though the underlying mechanism is not yet clear. However, adverse effects on local tissue cells (osteoblasts) were also observed.
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Affiliation(s)
- Ulrike Dapunt
- Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany
- Correspondence: ; Tel.: +49/6221-5625000
| | - Birgit Prior
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany;
| | - Christopher Oelkrug
- Oelkrug Enterprises UG (haftungsbeschraenkt), Gerhart Hauptmann Str. 10, 59387 Ascheberg, Germany;
| | - Jan Philippe Kretzer
- Laboratory of Biomechanics and Implant Research, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany;
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30
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Gosens R, Hiemstra PS, Adcock IM, Bracke KR, Dickson RP, Hansbro PM, Krauss-Etschmann S, Smits HH, Stassen FRM, Bartel S. Host-microbe cross-talk in the lung microenvironment: implications for understanding and treating chronic lung disease. Eur Respir J 2020; 56:13993003.02320-2019. [PMID: 32430415 PMCID: PMC7439216 DOI: 10.1183/13993003.02320-2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 04/20/2020] [Indexed: 12/15/2022]
Abstract
Chronic respiratory diseases are highly prevalent worldwide and will continue to rise in the foreseeable future. Despite intensive efforts over recent decades, the development of novel and effective therapeutic approaches has been slow. However, there is new and increasing evidence that communities of micro-organisms in our body, the human microbiome, are crucially involved in the development and progression of chronic respiratory diseases. Understanding the detailed mechanisms underlying this cross-talk between host and microbiota is critical for development of microbiome- or host-targeted therapeutics and prevention strategies. Here we review and discuss the most recent knowledge on the continuous reciprocal interaction between the host and microbes in health and respiratory disease. Furthermore, we highlight promising developments in microbiome-based therapies and discuss the need to employ more holistic approaches of restoring both the pulmonary niche and the microbial community. The reciprocal interaction between microbes and host in the lung is increasingly recognised as an important determinant of health. The complexity of this cross-talk needs to be taken into account when studying diseases and developing future new therapies.https://bit.ly/2VKYUfT
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Affiliation(s)
- Reinoud Gosens
- University of Groningen, Dept of Molecular Pharmacology, GRIAC Research Institute, Groningen, The Netherlands
| | - Pieter S Hiemstra
- Dept of Pulmonology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Ian M Adcock
- Airways Disease, National Heart and Lung Institute, Imperial College London, London, UK
| | - Ken R Bracke
- Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Robert P Dickson
- Division of Pulmonary and Critical Care Medicine, Dept of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.,Michigan Center for Integrative Research in Critical Care, Ann Arbor, MI, USA
| | - Philip M Hansbro
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and the University of Newcastle, Newcastle, Australia.,Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, Sydney, Australia
| | - Susanne Krauss-Etschmann
- Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, Airway Research Center North, Member of the German Center for Lung Research (DZL), Borstel, Germany.,Institute for Experimental Medicine, Christian-Albrechts-Universitaet zu Kiel, Kiel, Germany
| | - Hermelijn H Smits
- Dept of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frank R M Stassen
- Dept of Medical Microbiology, NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Sabine Bartel
- Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, Airway Research Center North, Member of the German Center for Lung Research (DZL), Borstel, Germany .,University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, GRIAC Research Institute, Groningen, The Netherlands
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31
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Bloxham CJ, Foster SR, Thomas WG. A Bitter Taste in Your Heart. Front Physiol 2020; 11:431. [PMID: 32457649 PMCID: PMC7225360 DOI: 10.3389/fphys.2020.00431] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/08/2020] [Indexed: 12/11/2022] Open
Abstract
The human genome contains ∼29 bitter taste receptors (T2Rs), which are responsible for detecting thousands of bitter ligands, including toxic and aversive compounds. This sentinel function varies between individuals and is underpinned by naturally occurring T2R polymorphisms, which have also been associated with disease. Recent studies have reported the expression of T2Rs and their downstream signaling components within non-gustatory tissues, including the heart. Though the precise role of T2Rs in the heart remains unclear, evidence points toward a role in cardiac contractility and overall vascular tone. In this review, we summarize the extra-oral expression of T2Rs, focusing on evidence for expression in heart; we speculate on the range of potential ligands that may activate them; we define the possible signaling pathways they activate; and we argue that their discovery in heart predicts an, as yet, unappreciated cardiac physiology.
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Affiliation(s)
- Conor J Bloxham
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia
| | - Simon R Foster
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Walter G Thomas
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia
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32
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Gopallawa I, Freund JR, Lee RJ. Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling. Cell Mol Life Sci 2020; 78:271-286. [PMID: 32172302 DOI: 10.1007/s00018-020-03494-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 01/30/2020] [Accepted: 02/24/2020] [Indexed: 01/22/2023]
Abstract
Bitter 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 (M[Formula: see text]s) 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 ~ threefold 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 M[Formula: see text] phagocytosis. Together, these data define M[Formula: see text] T2R signal transduction and support an immune recognition role for T2Rs in M[Formula: see text] cell physiology.
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Affiliation(s)
- Indiwari Gopallawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Ravdin, 5th Floor, Suite A , 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Jenna R Freund
- Department of Otorhinolaryngology, Head and Neck Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Ravdin, 5th Floor, Suite A , 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Robert J Lee
- Department of Otorhinolaryngology, Head and Neck Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Ravdin, 5th Floor, Suite A , 3400 Spruce Street, Philadelphia, PA, 19104, USA. .,Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
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33
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Guo J, Yoshida K, Ikegame M, Okamura H. Quorum sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone: An all-rounder in mammalian cell modification. J Oral Biosci 2020; 62:16-29. [DOI: 10.1016/j.job.2020.01.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 01/09/2020] [Accepted: 01/14/2020] [Indexed: 01/17/2023]
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34
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Wang Q, Liszt KI, Depoortere I. Extra-oral bitter taste receptors: New targets against obesity? Peptides 2020; 127:170284. [PMID: 32092303 DOI: 10.1016/j.peptides.2020.170284] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/10/2020] [Accepted: 02/20/2020] [Indexed: 12/13/2022]
Abstract
Taste perception on the tongue is essential to help us to identify nutritious or potential toxic food substances. Emerging evidence has demonstrated the expression and function of bitter taste receptors (TAS2Rs) in a wide range of extra-oral tissues. In particular, TAS2Rs in gastrointestinal enteroendocrine cells control the secretion of appetite regulating gut hormones and influence hunger and food intake. Furthermore, these effects may be reinforced by the presence of TAS2Rs on intestinal smooth muscle cells, adipocytes and the brain. This review summarises how activation of extra-oral TAS2Rs can influence appetite and body weight control and how obesity impacts the expression and function of TAS2Rs. Region-selective targeting of bitter taste receptors may be promising targets for the treatment of obesity.
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Affiliation(s)
- Qiaoling Wang
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Kathrin I Liszt
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Inge Depoortere
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium.
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35
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Grassin-Delyle S, Salvator H, Mantov N, Abrial C, Brollo M, Faisy C, Naline E, Couderc LJ, Devillier P. Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists. Front Physiol 2019; 10:1267. [PMID: 31632299 PMCID: PMC6783802 DOI: 10.3389/fphys.2019.01267] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 09/19/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Bitter-taste receptors (TAS2Rs) are involved in airway relaxation but are also expressed in human blood leukocytes. We studied TAS2R expression and the effects of TAS2R agonists on the lipopolysaccharide (LPS)-induced cytokine release in human lung macrophages (LMs). METHODS Lung macrophages were isolated from patients undergoing surgery for carcinoma. We used RT-qPCR to measure transcripts of 16 TAS2Rs (TAS2Rs 3/4/5/7/8/9/10/14/19/20/31/38/39/43/45 and 46) in unstimulated and LPS-stimulated (10 ng.mL-1) LMs. The macrophages were also incubated with TAS2R agonists for 24 h. Supernatant levels of the cytokines TNF-α, CCL3, CXCL8 and IL-10 were measured using ELISAs. RESULTS The transcripts of all 16 TAS2Rs were detected in macrophages. The addition of LPS led to an increase in the expression of most TAS2Rs, which was significant for TAS2R7 and 38. Although the promiscuous TAS2R agonists, quinine and denatonium, inhibited the LPS-induced release of TNF-α, CCL3 and CXCL8, diphenidol was inactive. Partially selective agonists (dapsone, colchicine, strychnine, and chloroquine) and selective agonists [erythromycin (TAS2R10), phenanthroline (TAS2R5), ofloxacin (TAS2R9), and carisoprodol (TAS2R14)] also suppressed the LPS-induced cytokine release. In contrast, two other agonists [sodium cromoglycate (TAS2R20) and saccharin (TAS2R31 and 43)] were inactive. TAS2R agonists suppressed IL-10 production - suggesting that this anti-inflammatory cytokine is not involved in the inhibition of cytokine production. CONCLUSION Human LMs expressed TAS2Rs. Experiments with TAS2R agonists' suggested the involvement of TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39 and 40 in the inhibition of cytokine production. TAS2Rs may constitute new drug targets in inflammatory obstructive lung disease.
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Affiliation(s)
- Stanislas Grassin-Delyle
- Department of Airway Diseases, Foch Hospital, Suresnes, France
- INSERM UMR 1173, UFR Simone Veil - Santé, University Versailles Saint-Quentin, University of Paris-Saclay, Montigny-le-Bretonneux, France
| | - Hélène Salvator
- Department of Airway Diseases, Foch Hospital, Suresnes, France
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
| | - Nikola Mantov
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
| | - Charlotte Abrial
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
| | - Marion Brollo
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
| | - Christophe Faisy
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
| | - Emmanuel Naline
- Department of Airway Diseases, Foch Hospital, Suresnes, France
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
| | - Louis-Jean Couderc
- Department of Airway Diseases, Foch Hospital, Suresnes, France
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
| | - Philippe Devillier
- Department of Airway Diseases, Foch Hospital, Suresnes, France
- Laboratory of Research in Respiratory Pharmacology–UPRES EA 220, Foch Hospital, University Versailles Saint-Quentin, University of Paris-Saclay, Suresnes, France
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36
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Ano Y, Kita M, Kitaoka S, Furuyashiki T. Leucine-Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress. Nutrients 2019; 11:nu11092161. [PMID: 31505850 PMCID: PMC6770249 DOI: 10.3390/nu11092161] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 08/25/2019] [Accepted: 08/29/2019] [Indexed: 12/12/2022] Open
Abstract
The number of patients with mental illnesses is rapidly increasing, and daily lifestyle is closely associated with the development of symptoms. It is suggested that inflammatory molecules derived from microglia play crucial roles for the pathophysiology of depression. In the present study, we discovered that leucine–histidine (LH) dipeptide suppressed activation of primary microglia. The effects of LH dipeptide orally administered were measured using tail suspension test (TST) in mice injected with lipopolysaccharide and social interaction test in mice received social defeat stress. LH dipeptide reduced pro-inflammatory cytokines upon stimulation in microglia. Orally administered LH dipeptide was delivered to the brain and suppressed the production of pro-inflammatory cytokines in the brain and concomitant depression-like behavior in the TST. Moreover, oral administration of LH dipeptide suppressed the induction of depression- and anxiety-like behaviors induced by repeated social defeat stress. These results indicate that LH dipeptide suppressed the activation of microglia and ameliorated depression-associated emotional disturbances. Further, we found that LH dipeptide was abundant in various fermented products. Together with previous epidemiological reports that daily intake of these fermented foods is negatively associated with the incidence of psychiatric diseases, our findings suggest that food rich in LH dipeptide may improve mental health.
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Affiliation(s)
- Yasuhisa Ano
- Research Laboratories for Health Science & Food Technologies, Kirin Holdings Company Ltd, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan.
| | - Masahiro Kita
- Research Laboratories for Health Science & Food Technologies, Kirin Holdings Company Ltd, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan.
| | - Shiho Kitaoka
- Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
- Japan Agency for Medical Research and Development (AMED)-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.
| | - Tomoyuki Furuyashiki
- Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
- Japan Agency for Medical Research and Development (AMED)-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.
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37
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Nayak AP, Villalba D, Deshpande DA. Bitter Taste Receptors: an Answer to Comprehensive Asthma Control? Curr Allergy Asthma Rep 2019; 19:48. [PMID: 31486942 DOI: 10.1007/s11882-019-0876-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Asthma is marked by peculiar pathological features involving airway contraction, an impinging inflammation in the lungs, and an inexorably progressive remodeling of pulmonary architecture. Current medications for management of asthma exacerbations fail to optimally mitigate these pathologies, which is partly due to the intrinsic heterogeneity in the development and progression of asthma within different populations. In recent years, the discovery of the ectopic expression of TAS2Rs in extraoral tissues and different cell types, combined with significant strides in gaining mechanistic understanding into receptor signaling and function, has revealed the potential to target TAS2Rs for asthma relief. RECENT FINDINGS TAS2R activation leads to relaxation of airway smooth muscle cells and bronchodilation. In addition, findings from preclinical studies in murine model of asthma suggest that TAS2R agonists inhibit allergen-induced airway inflammation, remodeling, and hyperresponsiveness. In this review, we expand on the opportunity presented by TAS2Rs in the development of a comprehensive asthma treatment that overcomes the limitations set forth by current asthma therapeutics.
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Affiliation(s)
- Ajay P Nayak
- Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, Room 543, 1020 Locust Street, Philadelphia, PA, 19107, USA
| | - Dominic Villalba
- Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, Room 543, 1020 Locust Street, Philadelphia, PA, 19107, USA
| | - Deepak A Deshpande
- Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, Room 543, 1020 Locust Street, Philadelphia, PA, 19107, USA.
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38
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Carey RM, Lee RJ. Taste Receptors in Upper Airway Innate Immunity. Nutrients 2019; 11:nu11092017. [PMID: 31466230 PMCID: PMC6770031 DOI: 10.3390/nu11092017] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 08/19/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
Taste receptors, first identified on the tongue, are best known for their role in guiding our dietary preferences. The expression of taste receptors for umami, sweet, and bitter have been demonstrated in tissues outside of the oral cavity, including in the airway, brain, gastrointestinal tract, and reproductive organs. The extra-oral taste receptor chemosensory pathways and the endogenous taste receptor ligands are generally unknown, but there is increasing data suggesting that taste receptors are involved in regulating some aspects of innate immunity, and may potentially control the composition of the nasal microbiome in healthy individuals or patients with upper respiratory diseases like chronic rhinosinusitis (CRS). For this reason, taste receptors may serve as potential therapeutic targets, providing alternatives to conventional antibiotics. This review focuses on the physiology of sweet (T1R) and bitter (T2R) taste receptors in the airway and their activation by secreted bacterial products. There is particular focus on T2R38 in sinonasal ciliated cells, as well as the sweet and bitter receptors found on specialized sinonasal solitary chemosensory cells. Additionally, this review explores the impact of genetic variations in these receptors on the differential susceptibility of patients to upper airway infections, such as CRS.
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Affiliation(s)
- Ryan M Carey
- Department of Otorhinolaryngology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert J Lee
- Department of Otorhinolaryngology and Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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39
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Nayak AP, Shah SD, Michael JV, Deshpande DA. Bitter Taste Receptors for Asthma Therapeutics. Front Physiol 2019; 10:884. [PMID: 31379597 PMCID: PMC6647873 DOI: 10.3389/fphys.2019.00884] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 06/24/2019] [Indexed: 01/12/2023] Open
Abstract
Clinical management of asthma and chronic obstructive pulmonary disease (COPD) has primarily relied on the use of beta 2 adrenergic receptor agonists (bronchodilators) and corticosteroids, and more recently, monoclonal antibody therapies (biologics) targeting specific cytokines and their functions. Although these approaches provide relief from exacerbations, questions remain on their long-term efficacy and safety. Furthermore, current therapeutics do not address progressive airway remodeling (AR), a key pathological feature of severe obstructive lung disease. Strikingly, agonists of the bitter taste receptors (TAS2Rs) deliver robust bronchodilation, curtail allergen-induced inflammatory responses in the airways and regulate airway smooth muscle (ASM) cell proliferation and mitigate features of AR in vitro and in animal models. The scope of this review is to provide a comprehensive and systematic insight into our current understanding of TAS2Rs with an emphasis on the molecular events that ensue TAS2R activation in distinct airway cell types and expand on the pleiotropic effects of TAS2R targeting in mitigating various pathological features of obstructive lung diseases. Finally, we will discuss specific opportunities that could help the development of selective agonists for specific TAS2R subtypes in the treatment of asthma.
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Affiliation(s)
- Ajay P Nayak
- Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Medicine, Department of Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States
| | - Sushrut D Shah
- Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Medicine, Department of Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States
| | - James V Michael
- Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Medicine, Department of Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States
| | - Deepak A Deshpande
- Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Medicine, Department of Medicine, Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States
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40
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Taher S, Borja Y, Cabanela L, Costers VJ, Carson-Marino M, Bailes JC, Dhar B, Beckworth MT, Rabaglino MB, Post Uiterweer ED, Conrad KP. Cholecystokinin, gastrin, cholecystokinin/gastrin receptors, and bitter taste receptor TAS2R14: trophoblast expression and signaling. Am J Physiol Regul Integr Comp Physiol 2019; 316:R628-R639. [PMID: 30892908 PMCID: PMC6589605 DOI: 10.1152/ajpregu.00153.2018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 02/19/2019] [Accepted: 02/20/2019] [Indexed: 02/07/2023]
Abstract
We investigated expression of cholecystokinin (CCK) in humans and mice, and the bitter taste receptor TAS2R14 in the human placenta. Because CCK and gastrin activate the CCKBR receptor, we also explored placental gastrin expression. Finally, we investigated calcium signaling by CCK and TAS2R14. By RT-PCR, we found CCK/Cck and GAST/Gast mRNA expression in both normal human and mouse placentas, as well as in human trophoblast cell lines (TCL). Although both Cckar and -br mRNA were expressed in the mouse placenta, only CCKBR mRNA was detected in the human placenta and TCL. mRNA expression for TAS2R14 was also observed in the human placenta and TCL. Using immunohistochemistry, CCK protein was localized to the syncytiotrophoblast (ST) and extravillous trophoblast (EVT) in the human term placenta, and to trophoblast glycogen cells in mouse and human placentas. Gastrin and TAS2R14 proteins were also observed in ST and EVT of the human placenta. Both sulfated and nonsulfated CCK elicited a comparable rise in intracellular calcium in TCL, consistent with CCKBR expression. Three TAS2R14 agonists, flufenamic acid, chlorhexidine, and diphenhydramine, also evoked rises in intracellular calcium in TCL. These results establish CCK, gastrin, and their receptor(s) in both human and mouse placentas, and TAS2R14 in the human placenta. Both CCK and TAS2R14 agonists increased intracellular calcium in human TCL. Although the roles of these ligands and receptors, and their potential cross talk in normal and pathological placentas, are currently unknown, this study opens new avenues for placental research.
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MESH Headings
- Animals
- Calcium Signaling
- Cell Line
- Cholecystokinin/genetics
- Cholecystokinin/metabolism
- Cholecystokinin/pharmacology
- Female
- Gastrins/genetics
- Gastrins/metabolism
- Gene Expression Regulation, Developmental
- Humans
- Ligands
- Mice
- Mice, Inbred C57BL
- Pregnancy
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptor, Cholecystokinin B/genetics
- Receptor, Cholecystokinin B/metabolism
- Receptors, Cholecystokinin/agonists
- Receptors, Cholecystokinin/genetics
- Receptors, Cholecystokinin/metabolism
- Receptors, G-Protein-Coupled/agonists
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction/drug effects
- Trophoblasts/drug effects
- Trophoblasts/metabolism
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Affiliation(s)
- Shèdy Taher
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Yamilette Borja
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Lucía Cabanela
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Vincent J Costers
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Morgan Carson-Marino
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Julie C Bailes
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Biswadeep Dhar
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Mark T Beckworth
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
| | - Maria B Rabaglino
- Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas y Técnicas, Pabellón de Biología Celular, Córdoba , Argentina
| | - Emiel D Post Uiterweer
- Department of Obstetrics and Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht , Utrecht , The Netherlands
| | - Kirk P Conrad
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, and D. H. Barron Reproductive and Perinatal Biology Research Program, Gainesville, Florida
- Department of Obstetrics and Gynecology, University of Florida College of Medicine , Gainesville, Florida
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41
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Tran HTT, Herz C, Ruf P, Stetter R, Lamy E. Human T2R38 Bitter Taste Receptor Expression in Resting and Activated Lymphocytes. Front Immunol 2018; 9:2949. [PMID: 30619309 PMCID: PMC6297872 DOI: 10.3389/fimmu.2018.02949] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 11/30/2018] [Indexed: 12/02/2022] Open
Abstract
The human G-protein-coupled bitter taste receptor T2R38 has recently been demonstrated to be expressed on peripheral blood neutrophils, monocytes and lymphocytes. To further define a potential contribution of the T2R38 receptor in adaptive immune response, the objective of this study was to analyze its expression in resting and activated lymphocytes and T cell subpopulations. Freshly isolated PBMC from healthy donors were used for expression analysis by flow cytometry. Quantum™ MESF beads were applied for quantification in absolute fluorescence units. Activation methods of T cells were anti-CD3/CD28, phytohaemagglutinin (PHA) or phorbol 12-myristate 13-acetate (PMA) together with ionomycin. Lymphocytes from young donors expressed higher levels of T2R38 compared to the elderly. CD3+ T cells expressed higher levels that CD19+ B cells. Receptor expression followed T cell activation with an upregulation within 24 h and a peak at 72 h. Higher levels of T2R38 were produced in lymphocytes by stimulation with anti-CD3/CD28 compared to PHA or PMA/ionomycin. Both subpopulations of CD4+ as well as CD8+ T cells were found to express the T2R38 receptor; this was higher in CD4+ than CD8+ cells; the amount of T2R38 in central and effector memory cells was higher as compared to naïve cells, although this was not statistically significant for CD8+ cells without prior activation by anti-CD3/CD28. Upon treatment of PBMC with the natural T2R38 agonist goitrin Calcium flux was activated in the lymphocyte population with functional T2R38 receptor at >20 μM which was completely blocked by phospholipase Cβ-2 inhibitor U73211. Further, goitrin selectively inhibited TNF-alpha secretion in PBMC with functional T2R38. This quantitative analysis of T2R38 expression in distinct PBMC subsets may provide a basis for understanding the significance of bitter compounds in immune modulation. Whether these findings can have implications for the treatment of inflammatory and immunologic disorders by bitter tasting pharmaceuticals or foods needs further investigation.
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Affiliation(s)
- Hoai T T Tran
- Molecular Preventive Medicine, Institute for Infection Prevention and Hospital Epidemiology, University Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs-University, Freiburg, Germany
| | - Corinna Herz
- Molecular Preventive Medicine, Institute for Infection Prevention and Hospital Epidemiology, University Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Patrick Ruf
- Molecular Preventive Medicine, Institute for Infection Prevention and Hospital Epidemiology, University Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rebecca Stetter
- Molecular Preventive Medicine, Institute for Infection Prevention and Hospital Epidemiology, University Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Evelyn Lamy
- Molecular Preventive Medicine, Institute for Infection Prevention and Hospital Epidemiology, University Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
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42
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Turkina MV, Vikström E. Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of Pseudomonas aeruginosa Infections. J Innate Immun 2018; 11:263-279. [PMID: 30428481 DOI: 10.1159/000494069] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 09/24/2018] [Indexed: 12/11/2022] Open
Abstract
Cell-to-cell signaling via small molecules is an essential process to coordinate behavior in single species within a community, and also across kingdoms. In this review, we discuss the quorum sensing (QS) systems used by the opportunistic pathogen Pseudomonas aeruginosa to sense bacterial population density and fitness, and regulate virulence, biofilm development, metabolite acquisition, and mammalian host defense. We also focus on the role of N-acylhomoserine lactone-dependent QS signaling in the modulation of innate immune responses connected together via calcium signaling, homeostasis, mitochondrial and cytoskeletal dynamics, and governing transcriptional and proteomic responses of host cells. A future perspective emphasizes the need for multidisciplinary efforts to bring current knowledge of QS into a more detailed understanding of the communication between bacteria and host, as well as into strategies to prevent and treat P. aeruginosa infections and reduce the rate of antibiotic resistance.
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Affiliation(s)
- Maria V Turkina
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Elena Vikström
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden,
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43
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Zhang XS, Li J, Krautkramer KA, Badri M, Battaglia T, Borbet TC, Koh H, Ng S, Sibley RA, Li Y, Pathmasiri W, Jindal S, Shields-Cutler RR, Hillmann B, Al-Ghalith GA, Ruiz VE, Livanos A, van 't Wout AB, Nagalingam N, Rogers AB, Sumner SJ, Knights D, Denu JM, Li H, Ruggles KV, Bonneau R, Williamson RA, Rauch M, Blaser MJ. Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity. eLife 2018; 7:37816. [PMID: 30039798 PMCID: PMC6085123 DOI: 10.7554/elife.37816] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 07/12/2018] [Indexed: 12/18/2022] Open
Abstract
The early-life intestinal microbiota plays a key role in shaping host immune system development. We found that a single early-life antibiotic course (1PAT) accelerated type 1 diabetes (T1D) development in male NOD mice. The single course had deep and persistent effects on the intestinal microbiome, leading to altered cecal, hepatic, and serum metabolites. The exposure elicited sex-specific effects on chromatin states in the ileum and liver and perturbed ileal gene expression, altering normal maturational patterns. The global signature changes included specific genes controlling both innate and adaptive immunity. Microbiome analysis revealed four taxa each that potentially protect against or accelerate T1D onset, that were linked in a network model to specific differences in ileal gene expression. This simplified animal model reveals multiple potential pathways to understand pathogenesis by which early-life gut microbiome perturbations alter a global suite of intestinal responses, contributing to the accelerated and enhanced T1D development.
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Affiliation(s)
- Xue-Song Zhang
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Jackie Li
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Kimberly A Krautkramer
- Department of Biomolecular Chemistry, Wisconsin Institute for Discovery, University of Wisconsin School of Medicine and Public Health, Madison, United States
| | - Michelle Badri
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States.,Center for Data Science, New York University, New York, United States
| | - Thomas Battaglia
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Timothy C Borbet
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Hyunwook Koh
- Department of Population Health, New York University Langone Medical Center, New York, United States
| | - Sandy Ng
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Rachel A Sibley
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Yuanyuan Li
- Nutrition Research Institute, University of North Carolina at Chapel Hill School of Public Health, Kannapolis, United States
| | - Wimal Pathmasiri
- Nutrition Research Institute, University of North Carolina at Chapel Hill School of Public Health, Kannapolis, United States
| | - Shawn Jindal
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Robin R Shields-Cutler
- Computer Science and Engineering, BioTechnology Institute, University of Minnesota, St. Paul, United States
| | - Ben Hillmann
- Computer Science and Engineering, BioTechnology Institute, University of Minnesota, St. Paul, United States
| | - Gabriel A Al-Ghalith
- Computer Science and Engineering, BioTechnology Institute, University of Minnesota, St. Paul, United States
| | - Victoria E Ruiz
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Alexandra Livanos
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Angélique B van 't Wout
- Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
| | - Nabeetha Nagalingam
- Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
| | - Arlin B Rogers
- Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, United States
| | - Susan Jenkins Sumner
- Nutrition Research Institute, University of North Carolina at Chapel Hill School of Public Health, Kannapolis, United States
| | - Dan Knights
- Computer Science and Engineering, BioTechnology Institute, University of Minnesota, St. Paul, United States
| | - John M Denu
- Department of Biomolecular Chemistry, Wisconsin Institute for Discovery, University of Wisconsin School of Medicine and Public Health, Madison, United States
| | - Huilin Li
- Department of Population Health, New York University Langone Medical Center, New York, United States
| | - Kelly V Ruggles
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States
| | - Richard Bonneau
- Center for Data Science, New York University, New York, United States
| | - R Anthony Williamson
- Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
| | - Marcus Rauch
- Janssen Prevention Center London, Janssen Pharmaceutical Companies of Johnson and Johnson, London, United Kingdom
| | - Martin J Blaser
- Department of Medicine, New York University Langone Medical Center, New York, United States.,Human Microbiome Program, New York University Langone Medical Center, New York, United States.,Department of Microbiology, New York Uniersity Langone Medical Center, New York, United States
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Jaggupilli A, Singh N, De Jesus VC, Gounni MS, Dhanaraj P, Chelikani P. Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics. FASEB J 2018; 33:501-517. [PMID: 30011231 DOI: 10.1096/fj.201800521rr] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Many medications including antibiotics taste bitter. The potency of these antibiotics on the 25 bitter taste receptors (T2Rs) in humans remains poorly understood. Here we characterize by sensory and structure-function analyses how antibiotics frequently used to treat airway infections in cystic fibrosis activate multiple human T2Rs. The potency of the broad-spectrum antibiotics, tobramycin, levofloxacin, and azithromycin on the highly expressed T2Rs in airways, T2R4, T2R14, and T2R20 was pursued. The amino acids and structural features of T2R4, T2R14, and T2R20 important for antibiotic binding were characterized by mutational analysis in heterologous cell-based assays. Strikingly, extracellular loop 2 in T2Rs performs a key function in binding to antibiotics with contribution from residues in transmembrane helices. Our results suggest that different antibiotics activate multiple T2Rs with different potencies. An understanding of the nonantibiotic and physiologic effects mediated through T2Rs on the host cells is much needed.-Jaggupilli, A., Singh, N., De Jesus, V. C., Gounni, M. S., Dhanaraj, P., Chelikani, P. Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics.
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Affiliation(s)
- Appalaraju Jaggupilli
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Nisha Singh
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Vivianne Cruz De Jesus
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Mohamed Soussi Gounni
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Premnath Dhanaraj
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Prashen Chelikani
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
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45
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Freund JR, Mansfield CJ, Doghramji LJ, Adappa ND, Palmer JN, Kennedy DW, Reed DR, Jiang P, Lee RJ. Activation of airway epithelial bitter taste receptors by Pseudomonas aeruginosa quinolones modulates calcium, cyclic-AMP, and nitric oxide signaling. J Biol Chem 2018; 293:9824-9840. [PMID: 29748385 DOI: 10.1074/jbc.ra117.001005] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 04/17/2018] [Indexed: 12/12/2022] Open
Abstract
Bitter taste receptors (taste family 2 bitter receptor proteins; T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. We have shown previously that airway epithelial cells express several T2Rs that activate innate immune responses that may be important for treatment of airway diseases such as chronic rhinosinusitis. It is imperative to more clearly understand what compounds activate airway T2Rs as well as their full range of functions. T2R isoforms in airway motile cilia (T2R4, -14, -16, and -38) produce bactericidal levels of nitric oxide (NO) that also increase ciliary beating, promoting clearance of mucus and trapped pathogens. Bacterial quorum-sensing acyl-homoserine lactones activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum-sensing molecule used by Pseudomonas aeruginosa To elucidate whether bacterial quinolones activate airway T2Rs, we analyzed calcium, cAMP, and NO dynamics using a combination of fluorescent indicator dyes and FRET-based protein biosensors. T2R-transfected HEK293T cells, several lung epithelial cell lines, and primary sinonasal cells grown and differentiated at the air-liquid interface were tested with 2-heptyl-3-hydroxy-4-quinolone (known as Pseudomonas quinolone signal; PQS), 2,4-dihydroxyquinolone, and 4-hydroxy-2-heptylquinolone (HHQ). In HEK293T cells, PQS activated T2R4, -16, and -38, whereas HHQ activated T2R14. 2,4-Dihydroxyquinolone had no effect. PQS and HHQ increased calcium and decreased both baseline and stimulated cAMP levels in cultured and primary airway cells. In primary cells, PQS and HHQ activated levels of NO synthesis previously shown to be bactericidal. This study suggests that airway T2R-mediated immune responses are activated by bacterial quinolones as well as acyl-homoserine lactones.
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Affiliation(s)
- Jenna R Freund
- From the Departments of Otorhinolaryngology-Head and Neck Surgery and
| | | | | | - Nithin D Adappa
- From the Departments of Otorhinolaryngology-Head and Neck Surgery and
| | - James N Palmer
- From the Departments of Otorhinolaryngology-Head and Neck Surgery and
| | - David W Kennedy
- From the Departments of Otorhinolaryngology-Head and Neck Surgery and
| | - Danielle R Reed
- the Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104
| | - Peihua Jiang
- the Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104
| | - Robert J Lee
- From the Departments of Otorhinolaryngology-Head and Neck Surgery and .,Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104 and
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Hu Z, Shao S, Zheng C, Sun Z, Shi J, Yu J, Qi Z, Shi K. Induction of systemic resistance in tomato against Botrytis cinerea by N-decanoyl-homoserine lactone via jasmonic acid signaling. PLANTA 2018; 247:1217-1227. [PMID: 29445868 DOI: 10.1007/s00425-018-2860-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 02/06/2018] [Indexed: 05/16/2023]
Abstract
N-decanoyl-homoserine lactone activates plant systemic resistance against Botrytis cinerea in tomato plants, which is largely dependent on jasmonic acid biosynthesis and signal transduction pathways. Rhizosphere bacteria secrete N-acylated-homoserine lactones (AHLs), a type of specialized quorum-sensing signal molecule, to coordinate their population density during communication with their eukaryotic hosts. AHLs behave as low molecular weight ligands that are sensed by plants and promote the host's resistance against foliar pathogens. In this study, we report on N-decanoyl-homoserine lactone (DHL), which is a type of AHL that induces systemic immunity in tomato plants and protects the host organism against the necrotrophic fungus Botrytis cinerea. Upon DHL treatment, tomato endogenous jasmonic acid (JA) biosynthesis (rather than salicylic acid biosynthesis) and signal transduction were significantly activated. Strikingly, the DHL-induced systemic resistance against B. cinerea was blocked in the tomato JA biosynthesis mutant spr2 and JA signaling gene-silenced plants. Our findings highlight the role of DHL in systemic resistance against economically important necrotrophic pathogens and suggest that DHL-induced immunity against B. cinerea is largely dependent on the JA signaling pathway. Manipulation of DHL-induced resistance is an attractive disease management strategy that could potentially be used to enhance disease resistance in diverse plant species.
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Affiliation(s)
- Zhangjian Hu
- Department of Horticulture, Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China
| | - Shujun Shao
- Department of Horticulture, Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China
| | - Chenfei Zheng
- Department of Horticulture, Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China
| | - Zenghui Sun
- Department of Horticulture, Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China
| | - Junying Shi
- Department of Horticulture, Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China
| | - Jingquan Yu
- Department of Horticulture, Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China
| | - Zhenyu Qi
- Experimental Station of Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China
| | - Kai Shi
- Department of Horticulture, Zhejiang University, 866 Yuhangtang Road, 310058, Hangzhou, People's Republic of China.
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47
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Carey RM, Workman AD, Yan CH, Chen B, Adappa ND, Palmer JN, Kennedy DW, Lee RJ, Cohen NA. Sinonasal T2R-mediated nitric oxide production in response to Bacillus cereus. Am J Rhinol Allergy 2018; 31:211-215. [PMID: 28716170 DOI: 10.2500/ajra.2017.31.4453] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
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.
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Affiliation(s)
- Ryan M Carey
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Cantone E, Negri R, Roscetto E, Grassia R, Catania MR, Capasso P, Maffei M, Soriano AA, Leone CA, Iengo M, Greco L. In Vivo Biofilm Formation, Gram-Negative Infections and TAS2R38 Polymorphisms in CRSw NP Patients. Laryngoscope 2018; 128:E339-E345. [PMID: 29570813 DOI: 10.1002/lary.27175] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 01/22/2018] [Accepted: 02/12/2018] [Indexed: 01/11/2023]
Abstract
OBJECTIVES Among the predisposing factors implicated in the immune response to airway bacterial infections, genetic variations of the bitter taste receptor TAS2R38, which is expressed in the cilia of the human sinonasal epithelial cells, seem to be associated with susceptibility to chronic rhinosinusitis (CRS) and in vitro biofilm formation. Polymorphisms in TAS2R38 generate two common haplotypes: the nonfunctional AVI (Alanine, Valine, Isoleucine) and the functional PAV (Proline, Alanine, Valine) alleles, with the latter protecting against gram-negative sinonasal infections. The aim of this study is to investigate for the first time the relevance of TAS2R38 genetic variants in the susceptibility to bacterial infections associated with in vivo biofilm formation in chronic rhinosinusitis with nasal polyps (CRSwNP) patients. STUDY DESIGN A prospective study on 100 adult patients undergoing functional endoscopic sinus surgery (FESS) for CRSwNP. METHODS Propylthiouracile (PROP) testing and TAS2R38 genotyping were applied to characterize patients for receptor functionality. Sinonasal mucosa samples were processed for microbiological examination and biofilm detection. RESULTS The nonfunctional genotype is more frequent among CRS patients than in the general population (25% vs. 18.4%, P = 0.034). Airway gram-negative infections are primarily associated with the AVI haplotype (88.9% vs. 11.1% PAV/PAV-functional genotype, P = 0.023). Biofilm formation is prevalent in CRS patients with the AVI nontaster phenotype (62.5% vs. 33.3% PAV taster or supertaster phenotype, P = 0.05). CONCLUSION Our findings confirm an inverse correlation between TAS2R38 functionality and gram-negative infections in Italian patients with CRSwNP. In addition, for the first time we demonstrated a relationship between in vivo microbial biofilm and TAS2R38 receptor variants. LEVEL OF EVIDENCE 2b. Laryngoscope, 128:E339-E345, 2018.
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Affiliation(s)
| | - Rossella Negri
- Department of Translational Medical Science (DISMET), Section of Pediatrics
| | - Emanuela Roscetto
- Department of Molecular Medicine and Medical Biotechnology, Section of Clinical Microbiology, University of Naples "Federico II"
| | - Rossella Grassia
- Department of Otolaryngology Head-Neck Surgery, Monaldi-Ospedale dei Colli, Naples, Italy
| | - Maria Rosaria Catania
- Department of Molecular Medicine and Medical Biotechnology, Section of Clinical Microbiology, University of Naples "Federico II"
| | - Pasquale Capasso
- Department of Otolaryngology Head-Neck Surgery, Monaldi-Ospedale dei Colli, Naples, Italy
| | - Marianna Maffei
- Department of Otolaryngology Head-Neck Surgery, Monaldi-Ospedale dei Colli, Naples, Italy
| | - Amata Amy Soriano
- Department of Molecular Medicine and Medical Biotechnology, Section of Clinical Microbiology, University of Naples "Federico II"
| | - Carlo Antonio Leone
- Department of Otolaryngology Head-Neck Surgery, Monaldi-Ospedale dei Colli, Naples, Italy
| | | | - Luigi Greco
- Department of Translational Medical Science (DISMET), Section of Pediatrics
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49
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Freund JR, Lee RJ. Taste receptors in the upper airway. World J Otorhinolaryngol Head Neck Surg 2018; 4:67-76. [PMID: 30035264 PMCID: PMC6051256 DOI: 10.1016/j.wjorl.2018.02.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 02/26/2018] [Indexed: 02/08/2023] Open
Abstract
Taste receptors were named for their originally-identified expression on the tongue and role in the sensation of taste (gustation). They are now known to be involved in many chemosensory processes outside the tongue. Expression of the receptors for bitter, sweet, and umami was recently identified in many organs, including the brain, airway, gastrointestinal tract, and reproductive systems. We do not yet know the full roles of these receptors in all of these tissues, nor do we know all of the endogenous ligands that activate them. However, taste receptors are emerging as potentially important therapeutic targets. Moreover, they may mediate some off target effects of drugs, as many medications in common clinical use are known to be bitter. The focus of this review is on recent basic and clinical data describing the expression of bitter (T2R) and sweet (T1R) receptors in the airway and their activation by secreted bacterial compounds. These receptors play important roles in innate immune nitric oxide production and antimicrobial peptide secretion, and may be useful targets for stimulating immune responses in the upper respiratory tract via topical therapies. Moreover, genetic variation in these receptors may play a role in the differential susceptibility of patients to certain types of respiratory infections as well as to differential outcomes in patients with chronic rhinosinusitis (CRS). CRS is a syndrome of chronic upper respiratory infection and inflammation and has a significant detrimental impact on patient quality of life. CRS treatment accounts for approximately 20% of adult antibiotic prescriptions and is thus a large driver of the public health crisis of antibiotic resistance. Taste receptors represent a novel class of therapeutic target to potentially stimulate endogenous immune responses and treat CRS patients without conventional antibiotics.
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Affiliation(s)
- Jenna R Freund
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert J Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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50
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Triantafillou V, Workman AD, Kohanski MA, Cohen NA. Taste Receptor Polymorphisms and Immune Response: A Review of Receptor Genotypic-Phenotypic Variations and Their Relevance to Chronic Rhinosinusitis. Front Cell Infect Microbiol 2018; 8:64. [PMID: 29564227 PMCID: PMC5845873 DOI: 10.3389/fcimb.2018.00064] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/21/2018] [Indexed: 01/22/2023] Open
Abstract
Bitter (T2R) and sweet taste (T1R) receptors have emerged as regulators of upper airway immune responses. Genetic variation of these taste receptors additionally confers susceptibility to infection and has been implicated in severity of disease in chronic rhinosinusitis (CRS). Ongoing taste receptor research has identified a variety of biologically active compounds that activate T1R and T2R receptors, increasing our understanding of not only additional receptor isoforms and their function but also how receptor function may contribute to the pathophysiology of CRS. This review will discuss the function of taste receptors in mediating airway immunity with a focus on recently described modulators of receptor function and directions for future research into the potential role of genotypic and phenotypic receptor variation as a predictor of airway disease and response to therapy.
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Affiliation(s)
- Vasiliki Triantafillou
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, United States
| | - Alan D Workman
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, United States
| | - Michael A Kohanski
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, United States
| | - Noam A Cohen
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, United States.,Department of Otorhinolaryngology-Head and Neck Surgery, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, United States
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