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

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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\(\Phi\)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\(\Phi\) phagocytosis. Together, these data define M\(\Phi\) T2R signal transduction and support an immune recognition role for T2Rs in M\(\Phi\) cell physiology.

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References

  1. Behrens M, Meyerhof W (2010) Oral and extraoral bitter taste receptors. Results Probl Cell Differ 52:87–99. https://doi.org/10.1007/978-3-642-14426-4_8

    Article  CAS  PubMed  Google Scholar 

  2. Lee RJ, Cohen NA (2015) Taste receptors in innate immunity. Cell Mol Life Sci 72:217–236. https://doi.org/10.1007/s00018-014-1736-7

    Article  CAS  PubMed  Google Scholar 

  3. Freund JR, Lee RJ (2018) Taste receptors in the upper airway. World J Otorhinolaryngol Head Neck Surg 4:67–76. https://doi.org/10.1016/j.wjorl.2018.02.004

    Article  PubMed  PubMed Central  Google Scholar 

  4. Carey RM, Lee RJ (2019) Taste receptors in upper airway innate immunity. Nutrients. https://doi.org/10.3390/nu11092017

    Article  PubMed  PubMed Central  Google Scholar 

  5. An SS, Liggett SB (2017) Taste and smell gpcrs in the lung: evidence for a previously unrecognized widespread chemosensory system. Cell Signal. https://doi.org/10.1016/j.cellsig.2017.02.002

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kim D, Woo JA, Geffken E, An SS, Liggett SB (2017) Coupling of airway smooth muscle bitter taste receptors to intracellular signaling and relaxation is via galphai1,2,3. Am J Respir Cell Mol Biol 56:762–771. https://doi.org/10.1165/rcmb.2016-0373OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Freund JR, Mansfield CJ, Doghramji LJ, Adappa ND, Palmer JN, Kennedy DW, Reed DR, Jiang P, Lee RJ (2018) Activation of airway epithelial bitter taste receptors by pseudomonas aeruginosa quinolones modulates calcium, cyclic-amp, and nitric oxide signaling. J Biol Chem 293:9824–9840. https://doi.org/10.1074/jbc.RA117.001005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hariri BM, McMahon DB, Chen B, Freund JR, Mansfield CJ, Doghramji LJ, Adappa ND, Palmer JN, Kennedy DW, Reed DR, Jiang P, Lee RJ (2017) Flavones modulate respiratory epithelial innate immunity: anti-inflammatory effects and activation of the t2r14 receptor. J Biol Chem 292:8484–8497. https://doi.org/10.1074/jbc.M116.771949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lee RJ, Xiong G, Kofonow JM, Chen B, Lysenko A, Jiang P, Abraham V, Doghramji L, Adappa ND, Palmer JN, Kennedy DW, Beauchamp GK, Doulias P-T, Ischiropoulos H, Kreindler JL, Reed DR, Cohen NA (2012) T2r38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J Clin Invest 122:4145–4159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lossow K, Hubner S, Roudnitzky N, Slack JP, Pollastro F, Behrens M, Meyerhof W (2016) Comprehensive analysis of mouse bitter taste receptors reveals different molecular receptive ranges for orthologous receptors in mice and humans. J Biol Chem 291:15358–15377. https://doi.org/10.1074/jbc.M116.718544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jaggupilli A, Singh N, Jesus VC, Duan K, Chelikani P (2018) Characterization of the binding sites for bacterial acyl homoserine lactones (ahls) on human bitter taste receptors (t2rs). ACS Infect Dis 4:1146–1156. https://doi.org/10.1021/acsinfecdis.8b00094

    Article  CAS  PubMed  Google Scholar 

  12. Adappa ND, Howland TJ, Palmer JN, Kennedy DW, Doghramji L, Lysenko A, Reed DR, Lee RJ, Cohen NA (2013) Genetics of the taste receptor t2r38 correlates with chronic rhinosinusitis necessitating surgical intervention. Int Forum Allergy Rhinol 3:184–187

    Article  PubMed  Google Scholar 

  13. Adappa ND, Zhang Z, Palmer JN, Kennedy DW, Doghramji L, Lysenko A, Reed DR, Scott T, Zhao NW, Owens D, Lee RJ, Cohen NA (2014) The bitter taste receptor t2r38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery. Int Forum Allergy Rhinol 4:3–7. https://doi.org/10.1002/alr.21253

    Article  PubMed  Google Scholar 

  14. Adappa ND, Farquhar D, Palmer JN, Kennedy DW, Doghramji L, Morris SA, Owens D, Mansfield C, Lysenko A, Lee RJ, Cowart BJ, Reed DR, Cohen NA (2015) Tas2r38 genotype predicts surgical outcome in nonpolypoid chronic rhinosinusitis. Int Forum Allergy Rhinol 6:25–33. https://doi.org/10.1002/alr.21666

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mfuna Endam L, Filali-Mouhim A, Boisvert P, Boulet LP, Bosse Y, Desrosiers M (2014) Genetic variations in taste receptors are associated with chronic rhinosinusitis: a replication study. Int Forum Allergy Rhinol 4:200–206. https://doi.org/10.1002/alr.21275

    Article  PubMed  Google Scholar 

  16. Rom DI, Christensen JM, Alvarado R, Sacks R, Harvey RJ (2017) The impact of bitter taste receptor genetics on culturable bacteria in chronic rhinosinusitis. Rhinology 55:90–94. https://doi.org/10.4193/Rhin16.181

    Article  CAS  PubMed  Google Scholar 

  17. Dzaman K, Zagor M, Sarnowska E, Krzeski A, Kantor I (2016) The correlation of tas2r38 gene variants with higher risk for chronic rhinosinusitis in polish patients. Otolaryngol Pol 70:13–18. https://doi.org/10.5604/00306657.1209438

    Article  PubMed  Google Scholar 

  18. Maurer S, Wabnitz GH, Kahle NA, Stegmaier S, Prior B, Giese T, Gaida MM, Samstag Y, Hansch GM (2015) Tasting pseudomonas aeruginosa biofilms: human neutrophils express the bitter receptor t2r38 as sensor for the quorum sensing molecule n-(3-oxododecanoyl)-l-homoserine lactone. Front Immunol 6:369. https://doi.org/10.3389/fimmu.2015.00369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gaida MM, Dapunt U, Hansch GM (2016) Sensing developing biofilms: the bitter receptor t2r38 on myeloid cells. Pathog Dis. https://doi.org/10.1093/femspd/ftw004

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tran HTT, Herz C, Ruf P, Stetter R, Lamy E (2018) Human t2r38 bitter taste receptor expression in resting and activated lymphocytes. Front Immunol 9:2949. https://doi.org/10.3389/fimmu.2018.02949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Malki A, Fiedler J, Fricke K, Ballweg I, Pfaffl MW, Krautwurst D (2015) Class i odorant receptors, tas1r and tas2r taste receptors, are markers for subpopulations of circulating leukocytes. J Leukoc Biol 97:533–545. https://doi.org/10.1189/jlb.2A0714-331RR

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grassin-Delyle S, Salvator H, Mantov N, Abrial C, Brollo M, Faisy C, Naline E, Couderc LJ, Devillier P (2019) Bitter taste receptors (tas2rs) in human lung macrophages: receptor expression and inhibitory effects of tas2r agonists. Front Physiol 10:1267. https://doi.org/10.3389/fphys.2019.01267

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bogdan C (2015) Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol 36:161–178. https://doi.org/10.1016/j.it.2015.01.003

    Article  CAS  PubMed  Google Scholar 

  24. Huang Z, Hoffmann FW, Fay JD, Hashimoto AC, Chapagain ML, Kaufusi PH, Hoffmann PR (2012) Stimulation of unprimed macrophages with immune complexes triggers a low output of nitric oxide by calcium-dependent neuronal nitric-oxide synthase. J Biol Chem 287:4492–4502. https://doi.org/10.1074/jbc.M111.315598

    Article  CAS  PubMed  Google Scholar 

  25. Reiling N, Ulmer AJ, Duchrow M, Ernst M, Flad HD, Hauschildt S (1994) Nitric oxide synthase: mRNA expression of different isoforms in human monocytes/macrophages. Eur J Immunol 24:1941–1944. https://doi.org/10.1002/eji.1830240836

    Article  CAS  PubMed  Google Scholar 

  26. Mühl H, Pfeilschifter J (2003) Endothelial nitric oxide synthase: a determinant of tnfα production by human monocytes/macrophages. Biochem Biophys Res Commun 310:677–680. https://doi.org/10.1016/j.bbrc.2003.09.039

    Article  CAS  PubMed  Google Scholar 

  27. Dugas B, Paul-Eugene N, Yamaoka K, Amirand C, Damais C, Kolb JP (1995) Il-4 induces camp and cgmp in human monocytic cells. Mediators Inflamm 4:298–305. https://doi.org/10.1155/S0962935195000482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schmidt HH, Warner TD, Nakane M, Forstermann U, Murad F (1992) Regulation and subcellular location of nitrogen oxide synthases in raw264.7 macrophages. Mol Pharmacol 41:615–624

    CAS  PubMed  Google Scholar 

  29. Connelly L, Jacobs AT, Palacios-Callender M, Moncada S, Hobbs AJ (2003) Macrophage endothelial nitric-oxide synthase autoregulates cellular activation and pro-inflammatory protein expression. J Biol Chem 278:26480–26487. https://doi.org/10.1074/jbc.M302238200

    Article  CAS  PubMed  Google Scholar 

  30. Fernandez-Boyanapalli R, McPhillips KA, Frasch SC, Janssen WJ, Dinauer MC, Riches DW, Henson PM, Byrne A, Bratton DL (2010) Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by ifn-gamma in a nitric oxide-dependent manner. J Immunol 185:4030–4041. https://doi.org/10.4049/jimmunol.1001778

    Article  CAS  PubMed  Google Scholar 

  31. Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, Macintyre AN, Goraksha-Hicks P, Rathmell JC, Makowski L (2014) Metabolic reprogramming of macrophages: Glucose transporter 1 (glut1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem 289:7884–7896. https://doi.org/10.1074/jbc.M113.522037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wiener A, Shudler M, Levit A, Niv MY (2012) Bitterdb: a database of bitter compounds. Nucleic Acids Res 40:D413–419. https://doi.org/10.1093/nar/gkr755

    Article  CAS  PubMed  Google Scholar 

  33. Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M (2010) The molecular receptive ranges of human tas2r bitter taste receptors. Chem Senses 35:157–170. https://doi.org/10.1093/chemse/bjp092

    Article  CAS  PubMed  Google Scholar 

  34. Zhang CH, Lifshitz LM, Uy KF, Ikebe M, Fogarty KE, ZhuGe R (2013) The cellular and molecular basis of bitter tastant-induced bronchodilation. PLoS Biol 11:e1001501. https://doi.org/10.1371/journal.pbio.1001501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Roland WS, Gouka RJ, Gruppen H, Driesse M, van Buren L, Smit G, Vincken JP (2014) 6-methoxyflavanones as bitter taste receptor blockers for htas2r39. PLoS ONE 9:e94451. https://doi.org/10.1371/journal.pone.0094451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Greene TA, Alarcon S, Thomas A, Berdougo E, Doranz BJ, Breslin PA, Rucker JB (2011) Probenecid inhibits the human bitter taste receptor tas2r16 and suppresses bitter perception of salicin. PLoS ONE 6:e20123. https://doi.org/10.1371/journal.pone.0020123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tewson PH, Martinka S, Shaner NC, Hughes TE, Quinn AM (2016) New dag and camp sensors optimized for live-cell assays in automated laboratories. J Biomol Screen 21:298–305. https://doi.org/10.1177/1087057115618608

    Article  CAS  PubMed  Google Scholar 

  38. Klarenbeek J, Goedhart J, van Batenburg A, Groenewald D, Jalink K (2015) Fourth-generation Epac-based FRET sensors for cAMP feature exceptional brightness, photostability and dynamic range: characterization of dedicated sensors for FLIM, for ratiometry and with high affinity. PLoS ONE 10:e0122513. https://doi.org/10.1371/journal.pone.0122513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Depry C, Allen MD, Zhang J (2011) Visualization of PKA activity in plasma membrane microdomains. Mol Biosyst 7:52–58. https://doi.org/10.1039/c0mb00079e

    Article  CAS  PubMed  Google Scholar 

  40. O'Neill LA, Pearce EJ (2016) Immunometabolism governs dendritic cell and macrophage function. J Exp Med 213:15–23. https://doi.org/10.1084/jem.20151570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mayevsky A, Rogatsky GG (2007) Mitochondrial function in vivo evaluated by NADH fluorescence: from animal models to human studies. Am J Physiol Cell Physiol 292:C615–640. https://doi.org/10.1152/ajpcell.00249.2006

    Article  CAS  PubMed  Google Scholar 

  42. Rossi AG, McCutcheon JC, Roy N, Chilvers ER, Haslett C, Dransfield I (1998) Regulation of macrophage phagocytosis of apoptotic cells by camp. J Immunol 160:3562–3568

    CAS  PubMed  Google Scholar 

  43. Yeager LA, Chopra AK, Peterson JW (2009) Bacillus anthracis edema toxin suppresses human macrophage phagocytosis and cytoskeletal remodeling via the protein kinase a and exchange protein activated by cyclic amp pathways. Infect Immun 77:2530–2543. https://doi.org/10.1128/IAI.00905-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peters-Golden M (2009) Putting on the brakes: cyclic amp as a multipronged controller of macrophage function. Sci Signal 2:pe37. https://doi.org/10.1126/scisignal.275pe37

    Article  CAS  PubMed  Google Scholar 

  45. Aronoff DM, Canetti C, Serezani CH, Luo M, Peters-Golden M (2005) Cutting edge: macrophage inhibition by cyclic amp (camp): differential roles of protein kinase a and exchange protein directly activated by camp-1. J Immunol 174:595–599. https://doi.org/10.4049/jimmunol.174.2.595

    Article  CAS  PubMed  Google Scholar 

  46. Roland WS, van Buren L, Gruppen H, Driesse M, Gouka RJ, Smit G, Vincken JP (2013) Bitter taste receptor activation by flavonoids and isoflavonoids: modeled structural requirements for activation of htas2r14 and htas2r39. J Agric Food Chem 61:10454–10466. https://doi.org/10.1021/jf403387p

    Article  CAS  PubMed  Google Scholar 

  47. Townsend EA, Meuchel LW, Thompson MA, Pabelick CM, Prakash YS (2011) Estrogen increases nitric-oxide production in human bronchial epithelium. J Pharmacol Exp Ther 339:815–824. https://doi.org/10.1124/jpet.111.184416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee RJ, Chen B, Redding KM, Margolskee RF, Cohen NA (2014) Mouse nasal epithelial innate immune responses to pseudomonas aeruginosa quorum-sensing molecules require taste signaling components. Innate Immun 20:606–617. https://doi.org/10.1177/1753425913503386

    Article  CAS  PubMed  Google Scholar 

  49. Kuroda Y, Ikeda R, Yamazaki T, Ito K, Uda K, Wakabayashi K, Watanabe T (2016) Activation of human bitter taste receptors by polymethoxylated flavonoids. Biosci Biotechnol Biochem 80:2014–2017. https://doi.org/10.1080/09168451.2016.1184558

    Article  CAS  PubMed  Google Scholar 

  50. Behrens M, Gu M, Fan S, Huang C, Meyerhof W (2017) Bitter substances from plants used in traditional Chinese medicine exert biased activation of human bitter taste receptors. Chem Biol Drug Des 91:422–433. https://doi.org/10.1111/cbdd.13089

    Article  CAS  PubMed  Google Scholar 

  51. Levit A, Nowak S, Peters M, Wiener A, Meyerhof W, Behrens M, Niv MY (2014) The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14. FASEB J 28:1181–1197. https://doi.org/10.1096/fj.13-242594

    Article  CAS  PubMed  Google Scholar 

  52. Clark AA, Liggett SB, Munger SD (2012) Extraoral bitter taste receptors as mediators of off-target drug effects. FASEB J 26:4827–4831. https://doi.org/10.1096/fj.12-215087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jun CD, Han MK, Kim UH, Chung HT (1996) Nitric oxide induces adp-ribosylation of actin in murine macrophages: association with the inhibition of pseudopodia formation, phagocytic activity, and adherence on a laminin substratum. Cell Immunol 174:25–34. https://doi.org/10.1006/cimm.1996.0290

    Article  CAS  PubMed  Google Scholar 

  54. Ke X, Terashima M, Nariai Y, Nakashima Y, Nabika T, Tanigawa Y (2001) Nitric oxide regulates actin reorganization through cGMP and Ca(2+)/calmodulin in raw 264.7 cells. Biochim Biophys Acta 1539:101–113. https://doi.org/10.1016/s0167-4889(01)00090-8

    Article  CAS  PubMed  Google Scholar 

  55. Liao WT, You HL, Li C, Chang JG, Chang SJ, Chen CJ (2015) Cyclic GMP-dependent protein kinase ii is necessary for macrophage m1 polarization and phagocytosis via toll-like receptor 2. J Mol Med (Berl) 93:523–533. https://doi.org/10.1007/s00109-014-1236-0

    Article  CAS  Google Scholar 

  56. Heinloth A, Brune B, Fischer B, Galle J (2002) Nitric oxide prevents oxidised ldl-induced p53 accumulation, cytochrome c translocation, and apoptosis in macrophages via guanylate cyclase stimulation. Atherosclerosis 162:93–101

    Article  CAS  PubMed  Google Scholar 

  57. Kiemer AK, Hartung T, Vollmar AM (2000) Cgmp-mediated inhibition of tnf-alpha production by the atrial natriuretic peptide in murine macrophages. J Immunol 165:175–181

    Article  CAS  PubMed  Google Scholar 

  58. Handa P, Tateya S, Rizzo NO, Cheng AM, Morgan-Stevenson V, Han CY, Clowes AW, Daum G, O'Brien KD, Schwartz MW, Chait A, Kim F (2011) Reduced vascular nitric oxide-cgmp signaling contributes to adipose tissue inflammation during high-fat feeding. Arterioscler Thromb Vasc Biol 31:2827–2835. https://doi.org/10.1161/ATVBAHA.111.236554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tateya S, Rizzo NO, Handa P, Cheng AM, Morgan-Stevenson V, Daum G, Clowes AW, Morton GJ, Schwartz MW, Kim F (2011) Endothelial no/cgmp/vasp signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding. Diabetes 60:2792–2801. https://doi.org/10.2337/db11-0255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Metukuri MR, Namas R, Gladstone C, Clermont T, Jefferson B, Barclay D, Hermus L, Billiar TR, Zamora R, Vodovotz Y (2009) Activation of latent transforming growth factor-beta1 by nitric oxide in macrophages: role of soluble guanylate cyclase and map kinases. Wound Repair Regen 17:578–588. https://doi.org/10.1111/j.1524-475X.2009.00509.x

    Article  PubMed  Google Scholar 

  61. Von Knethen A, Brune B (2002) Activation of peroxisome proliferator-activated receptor gamma by nitric oxide in monocytes/macrophages down-regulates p47phox and attenuates the respiratory burst. J Immunol 169:2619–2626

    Article  Google Scholar 

  62. Brune B, Dehne N, Grossmann N, Jung M, Namgaladze D, Schmid T, von Knethen A, Weigert A (2013) Redox control of inflammation in macrophages. Antioxid Redox Signal 19:595–637. https://doi.org/10.1089/ars.2012.4785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ichinose M, Sawada M, Maeno T (1994) Inhibitory effect of vasoactive intestinal peptide (vip) on phagocytosis in mouse peritoneal macrophages. Regul Pept 54:457–466. https://doi.org/10.1016/0167-0115(94)90543-6

    Article  CAS  PubMed  Google Scholar 

  64. Litwin DK, Wilson AK, Said SI (1992) Vasoactive intestinal polypeptide (vip) inhibits rat alveolar macrophage phagocytosis and chemotaxis in vitro. Regul Pept 40:63–74. https://doi.org/10.1016/0167-0115(92)90084-8

    Article  CAS  PubMed  Google Scholar 

  65. Takami S, Getchell TV, McLaughlin SK, Margolskee RF, Getchell ML (1994) Human taste cells express the g protein alpha-gustducin and neuron-specific enolase. Brain Res Mol Brain Res 22:193–203

    Article  CAS  PubMed  Google Scholar 

  66. McLaughlin SK, McKinnon PJ, Margolskee RF (1992) Gustducin is a taste-cell-specific g protein closely related to the transducins. Nature 357:563–569. https://doi.org/10.1038/357563a0

    Article  CAS  PubMed  Google Scholar 

  67. Foskett JK, White C, Cheung KH, Mak DO (2007) Inositol trisphosphate receptor ca2+ release channels. Physiol Rev 87:593–658

    Article  CAS  PubMed  Google Scholar 

  68. Yule DI, Straub SV, Bruce JI (2003) Modulation of ca2+ oscillations by phosphorylation of ins(1,4,5)p3 receptors. Biochem Soc Trans 31:954–957

    Article  CAS  PubMed  Google Scholar 

  69. Ma Z, Taruno A, Ohmoto M, Jyotaki M, Lim JC, Miyazaki H, Niisato N, Marunaka Y, Lee RJ, Hoff H, Payne R, Demuro A, Parker I, Mitchell CH, Henao-Mejia J, Tanis JE, Matsumoto I, Tordoff MG, Foskett JK (2018) Calhm3 is essential for rapid ion channel-mediated purinergic neurotransmission of gpcr-mediated tastes. Neuron 98(547–561):e510. https://doi.org/10.1016/j.neuron.2018.03.043

    Article  CAS  Google Scholar 

  70. McMahon DB, Workman AD, Kohanski MA, Carey RM, Freund JR, Hariri BM, Chen B, Doghramji LJ, Adappa ND, Palmer JN, Kennedy DW, Lee RJ (2018) Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating. FASEB J 32:155–167. https://doi.org/10.1096/fj.201700114RRR

    Article  CAS  PubMed  Google Scholar 

  71. Lee RJ, Hariri BM, McMahon DB, Chen B, Doghramji L, Adappa ND, Palmer JN, Kennedy DW, Jiang P, Margolskee RF, Cohen NA (2017) Bacterial d-amino acids suppress sinonasal innate immunity through sweet taste receptors in solitary chemosensory cells. Sci Signal. https://doi.org/10.1126/scisignal.aam7703

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by National Institutes of Health grants (R01DC016309, R21AI137484). Content is solely the responsibility of the authors and does not represent official views of the National Institutes of Health. The authors thank J. Riley (University of Pennsylvania Human Immunology Core, supported by P30-CA016520 and P30-AI045008) for access to monocytes and M. Victoria (University of Pennsylvania) for excellent assistance with MΦ culture and molecular biology and helpful comments on the manuscript. We thank D. McMahon and L.E. Kuek (University of Pennsylvania) for assistance with qPCR. We thank N. Cohen (University of Pennsylvania) for sharing reagents. The authors have no conflicts of interest to declare.

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  1. 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

    Indiwari Gopallawa, Jenna R. Freund & Robert J. Lee

  2. Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA

    Robert J. Lee

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Gopallawa, I., Freund, J.R. & Lee, R.J. Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling. Cell. Mol. Life Sci. 78, 271–286 (2021). https://doi.org/10.1007/s00018-020-03494-y

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