title: The M3 muscarinic receptor is required for optimal adaptive immunity to helminth and bacterial infection.
abstract: Innate immunity is regulated by cholinergic signalling through nicotinic acetylcholine receptors. We show here that signalling through the M3 muscarinic acetylcholine receptor (M3R) plays an important role in adaptive immunity to both Nippostrongylus brasiliensis and Salmonella enterica serovar Typhimurium, as M3R-/- mice were impaired in their ability to resolve infection with either pathogen. CD4 T cell activation and cytokine production were reduced in M3R-/- mice. Immunity to secondary infection with N. brasiliensis was severely impaired, with reduced cytokine responses in M3R-/- mice accompanied by lower numbers of mucus-producing goblet cells and alternatively activated macrophages in the lungs. Ex vivo lymphocyte stimulation of cells from intact BALB/c mice infected with N. brasiliensis and S. typhimurium with muscarinic agonists resulted in enhanced production of IL-13 and IFN-γ respectively, which was blocked by an M3R-selective antagonist. Our data therefore indicate that cholinergic signalling via the M3R is essential for optimal Th1 and Th2 adaptive immunity to infection.
authors: Institute of Infectious Disease and Molecular Medicine, International Centre for Genetic Engineering and Biotechnology and Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Matthew
authors: M
authors: Darby
authors: Department of Life Sciences, Sir Ernst Chain Building, South Kensington Campus, Imperial College London, London, United Kingdom.
authors: Corinna
authors: C
authors: Schnoeller
authors: Institute of Infectious Disease and Molecular Medicine, International Centre for Genetic Engineering and Biotechnology and Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Alykhan
authors: A
authors: Vira
authors: National Heart and Lung Institute, St.Mary's Campus, Praed Street, Imperial College London, London, United Kingdom.
authors: Fiona Jane
authors: FJ
authors: Culley
authors: National Heart and Lung Institute, St.Mary's Campus, Praed Street, Imperial College London, London, United Kingdom.
authors: Fiona
authors: F
authors: Culley
authors: Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.
authors: Saeeda
authors: S
authors: Bobat
authors: Institute of Infectious Disease and Molecular Medicine, International Centre for Genetic Engineering and Biotechnology and Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Erin
authors: E
authors: Logan
authors: Institute of Infectious Disease and Molecular Medicine, International Centre for Genetic Engineering and Biotechnology and Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Frank
authors: F
authors: Kirstein
authors: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Jürgen
authors: J
authors: Wess
authors: Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.
authors: Adam F
authors: AF
authors: Cunningham
authors: Institute of Infectious Disease and Molecular Medicine, International Centre for Genetic Engineering and Biotechnology and Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: Frank
authors: F
authors: Brombacher
authors: Department of Life Sciences, Sir Ernst Chain Building, South Kensington Campus, Imperial College London, London, United Kingdom.
authors: Murray E
authors: ME
authors: Selkirk
authors: Institute of Infectious Disease and Molecular Medicine, International Centre for Genetic Engineering and Biotechnology and Division of Immunology, University of Cape Town, Cape Town, South Africa.
authors: William G C
authors: WG
authors: Horsnell
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009559:Nippostrongylus / Q000276:immunology*; D043587:Receptor, Muscarinic M3 / Q000502:physiology*; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D043587:Receptor, Muscarinic M3
references: Bioorg Med Chem. 1999 Nov;7(11):2555-67
references: 10632066
references: J Leukoc Biol. 2000 Apr;67(4):457-63
references: 10770276
references: Jpn J Pharmacol. 2000 Oct;84(2):124-32
references: 11128034
references: J Neurosci. 2002 Dec 15;22(24):10627-32
references: 12486155
references: Nature. 2003 Jan 23;421(6921):384-8
references: 12508119
references: Trends Immunol. 2003 May;24(5):269-77
references: 12738422
references: J Immunol. 2003 Jul 15;171(2):948-54
references: 12847266
references: Prog Brain Res. 1993;98:293-301
references: 7504311
references: FASEB J. 1995 May;9(8):619-25
references: 7768353
references: J Immunol. 1996 May 1;156(9):3321-6
references: 8617956
references: Am J Physiol Gastrointest Liver Physiol. 2005 Apr;288(4):G609-15
references: 15528258
references: Prog Med Chem. 2005;43:105-36
references: 15850824
references: J Neuroimmunol. 2005 Jul;164(1-2):66-75
references: 15913791
references: Eur J Pharmacol. 2005 Jul 11;517(3):246-51
references: 15963492
references: Gastroenterology. 2005 Jul;129(1):131-41
references: 16012943
references: J Biochem. 2006 Mar;139(3):449-58
references: 16567410
references: PLoS Pathog. 2007 Jan;3(1):e1
references: 17222057
references: Life Sci. 2007 May 30;80(24-25):2314-9
references: 17383684
references: Nat Rev Drug Discov. 2007 Sep;6(9):721-33
references: 17762886
references: Eur Respir J. 2007 Oct;30(4):653-61
references: 17537779
references: J Neuroimmunol. 2008 Feb;194(1-2):83-8
references: 18190972
references: J Immunol. 2008 Sep 15;181(6):3984-93
references: 18768853
references: Nat Rev Immunol. 2009 Jun;9(6):418-28
references: 19461672
references: Immunology. 2010 Jul;130(3):388-98
references: 20408892
references: Infect Immun. 2010 Sep;78(9):3753-62
references: 20605978
references: Mucosal Immunol. 2011 Jan;4(1):83-92
references: 20737001
references: Br J Pharmacol. 2011 May;163(1):44-52
references: 21198547
references: Genes Immun. 2011 Apr;12(3):222-30
references: 21270829
references: J Exp Med. 2011 May 9;208(5):893-900
references: 21502330
references: Biomed Pharmacother. 2011 Jun;65(3):193-7
references: 21111564
references: J Neuroimmunol. 2011 Jul;236(1-2):47-56
references: 21665296
references: J Immunol. 2011 Aug 15;187(4):1553-65
references: 21734076
references: Science. 2011 Oct 7;334(6052):98-101
references: 21921156
references: J Innate Immun. 2011;3(6):543-9
references: 21912097
references: Eur J Immunol. 2012 Mar;42(3):580-8
references: 22259035
references: N Engl J Med. 2012 Sep 27;367(13):1198-207
references: 22938706
references: Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1410-5
references: 23297238
references: PLoS Pathog. 2014 Feb;10(2):e1003906
references: 24516382
references: Mucosal Immunol. 2014 Mar;7(2):239-48
references: 23778354
references: Am J Respir Cell Mol Biol. 2014 Apr;50(4):690-8
references: 24156289
references: Nat Immunol. 2014 Oct;15(10):938-46
references: 25173346