title: Mouse nasal epithelial innate immune responses to Pseudomonas aeruginosa quorum-sensing molecules require taste signaling components.
abstract: We previously observed that the human bitter taste receptor T2R38 is an important component of upper respiratory innate defense because it detects acyl homoserine lactone (AHL) quorum-sensing molecules secreted by Gram-negative bacteria. T2R38 activation in human sinonasal epithelial cells stimulates calcium and NO signals that increase mucociliary clearance, the major physical respiratory defense against inhaled pathogens. While mice do not have a clear T2R38 ortholog, they do have bitter taste receptors capable of responding to T2R38 agonists, suggesting that T2R-mediated innate immune mechanisms may be conserved in mice. We examined whether AHLs activate calcium and NO signaling in mouse nasal epithelial cells, and utilized pharmacology, as well as cells from knockout mice lacking important components of canonical taste signal transduction pathways, to determine if AHL-stimulated responses require taste signaling molecules. We found that AHLs stimulate calcium-dependent NO production that increases mucociliary clearance and thus likely serves an innate immune role against Gram-negative bacteria. These responses require PLCβ2 and TRPM5 taste signaling components, but not α-gustducin. These data suggest the mouse may be a useful model for further studies of T2R-mediated innate immunity.
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Monell Chemical Senses Center and Philadelphia VA Medical Center Surgical Services, Philadelphia, PA, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Redding
authors.affiliation: Monell Chemical Senses Center and Philadelphia VA Medical Center Surgical Services, Philadelphia, PA, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Margolskee
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA Surgical Services, Philadelphia Veterans Administration Medical Center, Philadelphia, PA, USA noam.cohen@uphs.upenn.edu.
authors.forename: Noam A
authors.initials: NA
authors.lastname: Cohen
mesh_terms: D054742:Acyl-Butyrolactones / Q000494:pharmacology; D000818:Animals; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000276:immunology*; D009569:Nitric Oxide / Q000502:physiology; D054799:Phospholipase C beta / Q000235:genetics / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000737:chemistry*; D053038:Quorum Sensing; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology; D013649:Taste / Q000187:drug effects* / Q000235:genetics; D015293:Transducin / Q000235:genetics
chemical_list: D054742:Acyl-Butyrolactones; D050053:TRPM Cation Channels; C498617:Trpm5 protein, mouse; C075192:gustducin; D009569:Nitric Oxide; D054799:Phospholipase C beta; C518037:Plcb2 protein, mouse; D015293:Transducin
keywords: Acyl-homoserine lactone; T2R bitter taste receptor; chronic rhinosinusitis; innate immunity; mucociliary clearance; nitric oxide
references.citation: Eur J Pharmacol. 2004 Apr 12;489(3):139-49
references.pmid: 15087236
references.citation: Semin Cell Dev Biol. 2013 Mar;24(3):215-21
references.pmid: 22947915
references.citation: FASEB J. 2012 Aug;26(8):3178-87
references.pmid: 22516297
references.citation: PLoS One. 2010 Aug 25;5(8):e12394
references.pmid: 20811630
references.citation: J Clin Invest. 1997 Jun 15;99(12):2818-25
references.pmid: 9185502
references.citation: Chem Senses. 2002 Oct;27(8):719-27
references.pmid: 12379596
references.citation: J Neurosci. 2004 Sep 1;24(35):7674-80
references.pmid: 15342734
references.citation: Assay Drug Dev Technol. 2010 Dec;8(6):703-13
references.pmid: 21158685
references.citation: Mol Microbiol. 1998 Oct;30(2):295-304
references.pmid: 9791175
references.citation: Free Radic Biol Med. 2004 Jun 1;36(11):1448-59
references.pmid: 15135182
references.citation: Int Forum Allergy Rhinol. 2011 Nov-Dec;1(6):438-44
references.pmid: 22144052
references.citation: Am Rev Respir Dis. 1970 Jul;102(1):48-52
references.pmid: 5427403
references.citation: Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1490-4
references.pmid: 7878006
references.citation: Am J Physiol Cell Physiol. 2006 Oct;291(4):C726-39
references.pmid: 16707556
references.citation: J Neurophysiol. 2002 Jun;87(6):3152-5
references.pmid: 12037215
references.citation: J Chem Inf Model. 2012 Jul 23;52(7):1875-85
references.pmid: 22656649
references.citation: Am J Rhinol. 2007 May-Jun;21(3):373-7
references.pmid: 17621826
references.citation: Curr Biol. 2005 Feb 22;15(4):322-7
references.pmid: 15723792
references.citation: Methods Mol Biol. 2011;742:77-92
references.pmid: 21547727
references.citation: Methods Mol Biol. 2013;945:109-21
references.pmid: 23097104
references.citation: J Biol Chem. 2002 Jan 4;277(1):1-4
references.pmid: 11696554
references.citation: Inflamm Res. 2007 Feb;56(2):58-69
references.pmid: 17431742
references.citation: Clin Allergy Immunol. 2007;20:1-13
references.pmid: 17534042
references.citation: Hum Mutat. 2005 Sep;26(3):199-204
references.pmid: 16086309
references.citation: Allergy Asthma Proc. 1996 Sep-Oct;17(5):283-6
references.pmid: 8922148
references.citation: Chem Senses. 2006 Mar;31(3):253-64
references.pmid: 16436689
references.citation: Ann Allergy Asthma Immunol. 2008 Oct;101(4):358-62
references.pmid: 18939722
references.citation: Physiol Genomics. 2005 Jul 14;22(2):139-49
references.pmid: 15886333
references.citation: Results Probl Cell Differ. 2010;52:87-99
references.pmid: 20865374
references.citation: Am J Rhinol Allergy. 2012 Jan-Feb;26(1):1-6
references.pmid: 22391065
references.citation: J Mol Model. 2006 Sep;12(6):931-41
references.pmid: 16607493
references.citation: Science. 2009 Aug 28;325(5944):1131-4
references.pmid: 19628819
references.citation: Am J Otolaryngol. 2007 Sep-Oct;28(5):334-7
references.pmid: 17826536
references.citation: Immunopharmacology. 1997 Aug;37(1):35-41
references.pmid: 9285242
references.citation: Otolaryngol Head Neck Surg. 2011 Feb;144(2):159-69
references.pmid: 21634057
references.citation: Immunol Allergy Clin North Am. 2009 Nov;29(4):631-43
references.pmid: 19879439
references.citation: Biochem Biophys Res Commun. 1991 Dec 16;181(2):852-7
references.pmid: 1721811
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8868-73
references.pmid: 11447270
references.citation: Rhinology. 2008 Mar;46(1):23-7
references.pmid: 18444488
references.citation: Biochem J. 2011 Aug 15;438(1):33-7
references.pmid: 21592089
references.citation: Curr Opin Neurobiol. 2000 Aug;10(4):519-27
references.pmid: 10981623
references.citation: FEBS Lett. 2008 Nov 12;582(27):3783-7
references.pmid: 18930056
references.citation: Am J Otolaryngol. 2004 Sep-Oct;25(5):323-8
references.pmid: 15334396
references.citation: Am Rev Respir Dis. 1988 Mar;137(3):726-41
references.pmid: 3278666
references.citation: Physiol Behav. 1994 Dec;56(6):1141-7
references.pmid: 7878083
references.citation: J Bacteriol. 1997 Sep;179(18):5756-67
references.pmid: 9294432
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2392-7
references.pmid: 11854532
references.citation: J Clin Invest. 2012 Nov;122(11):4145-59
references.pmid: 23041624
references.citation: J Bacteriol. 1999 Feb;181(4):1203-10
references.pmid: 9973347
references.citation: Int Forum Allergy Rhinol. 2013 Mar;3(3):184-7
references.pmid: 23322450
references.citation: Chem Senses. 2005 May;30(4):299-316
references.pmid: 15800219
references.citation: BMC Genet. 2005 Jun 20;6:36
references.pmid: 15967025
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3210-5
references.pmid: 20133764
references.citation: J Am Chem Soc. 2011 Apr 20;133(15):5966-75
references.pmid: 21434644
references.citation: Nature. 1992 Jun 18;357(6379):563-9
references.pmid: 1608467
references.citation: Nature. 1996 Jun 27;381(6585):796-800
references.pmid: 8657284
references.citation: Otolaryngol Head Neck Surg. 2007 Mar;136(3):348-56
references.pmid: 17321858
references.citation: Chem Senses. 2010 Feb;35(2):157-70
references.pmid: 20022913
references.citation: J Otolaryngol Head Neck Surg. 2011 Jun;40(3):232-7
references.pmid: 21518646
references.citation: Am J Rhinol. 2007 Sep-Oct;21(5):533-7
references.pmid: 17999784
references.citation: J Neurosci. 2003 Oct 29;23(30):9947-52
references.pmid: 14586025
references.citation: Biotechniques. 2007 Aug;43(2):195-6, 198, 200 passim
references.pmid: 17824387
references.citation: Annu Rev Physiol. 1990;52:137-55
references.pmid: 2184754
references.citation: BMC Pulm Med. 2011 Jan 13;11:3
references.pmid: 21232137
references.citation: J Allergy Clin Immunol. 2011 Dec;128(6):1207-1215.e1
references.pmid: 21982113
references.citation: Curr Protoc Mol Biol. 2010 Oct;Chapter 14:Unit14.20
references.pmid: 20890901
references.citation: Am J Respir Crit Care Med. 2003 Aug 1;168(3):281-6
references.pmid: 12702547
references.citation: Annu Rev Physiol. 2007;69:401-22
references.pmid: 16945069
references.citation: Behav Genet. 1986 Nov;16(6):605-10
references.pmid: 3566698
references.citation: J Neurophysiol. 2008 Jun;99(6):2929-37
references.pmid: 18417634
references.citation: Am J Rhinol. 2008 Jan-Feb;22(1):13-9
references.pmid: 18284853
references.citation: J Neurosci. 2007 May 23;27(21):5777-86
references.pmid: 17522321
references.citation: Otolaryngol Head Neck Surg. 2006 Apr;134(4):601-4
references.pmid: 16564380
references.citation: Am J Rhinol Allergy. 2009 Mar-Apr;23(2):159-61
references.pmid: 19401041
references.citation: Ann Otol Rhinol Laryngol. 2008 Jun;117(6):448-52
references.pmid: 18646442
references.citation: BMC Neurosci. 2009 Mar 12;10:20
references.pmid: 19284629
references.citation: Hum Pathol. 2011 Dec;42(12):1855-61
references.pmid: 21663943
references.citation: Am J Rhinol Allergy. 2011 Mar-Apr;25(2):e49-54
references.pmid: 21679499
references.citation: Thorax. 2003 Feb;58(2):175-82
references.pmid: 12554905
references.citation: Toxicol In Vitro. 2005 Feb;19(1):107-22
references.pmid: 15582362
references.citation: Am J Rhinol Allergy. 2012 Jul-Aug;26(4):255-9
references.pmid: 22801009
references.citation: Chem Senses. 2005 Jun;30(5):377-82
references.pmid: 15800216
references.citation: Chem Senses. 2003 Oct;28(8):695-704
references.pmid: 14627538
references.citation: Ann Otol Rhinol Laryngol Suppl. 2006 Sep;196:20-6
references.pmid: 17040014
references.citation: J Otolaryngol. 1999 Aug;28(4):197-204
references.pmid: 10461256
references.citation: Curr Opin Neurobiol. 1996 Aug;6(4):506-13
references.pmid: 8794107