Cholinergic stimulation of the immune system protects against lethal infection by Salmonella enterica serovar Typhimurium.
The cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival.
Fernandez-Cabezudo
Maria J
MJ
Department of Biochemistry, Faculty of Medicine & Health Sciences, UAE University, Al Ain, United Arab Emirates. mariac@uaeu.ac.ae
Lorke
Dietrich E
DE
Azimullah
Sheikh
S
Mechkarska
Milena
M
Hasan
Mohammed Y
MY
Petroianu
Georg A
GA
al-Ramadi
Basel K
BK
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D002452:Cell Count; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D058851:GPI-Linked Proteins; D007107:Immune System / Q000187:drug effects* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000382:microbiology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D010261:Paraoxon / Q000494:pharmacology / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000494:pharmacology; D012480:Salmonella Infections / Q000097:blood / Q000188:drug therapy / Q000382:microbiology* / Q000517:prevention & control*; D012486:Salmonella typhimurium / Q000472:pathogenicity; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects
C513728:4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D016207:Cytokines; D058851:GPI-Linked Proteins; D008070:Lipopolysaccharides; D010091:Oximes; D011726:Pyridinium Compounds; D003208:Concanavalin A; D009569:Nitric Oxide; D000110:Acetylcholinesterase; C548245:Ache protein, mouse; D010261:Paraoxon
Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11008-13
18669662
J Immunol. 1995 May 15;154(10):5320-30
7730635
Toxicol Appl Pharmacol. 2007 Feb 1;218(3):215-26
17196234
J Exp Med. 2005 Apr 4;201(7):1113-23
15809354
Nature. 2003 Jan 23;421(6921):384-8
12508119
Life Sci. 2007 May 30;80(24-25):2314-9
17383684
Infect Immun. 2000 Jun;68(6):3344-8
10816483
Bioorg Med Chem Lett. 2003 Oct 20;13(20):3545-7
14505667
J Immunol. 2001 Nov 1;167(9):5304-15
11673546
Infect Immun. 1998 Oct;66(10):4767-76
9746577
Cell Mol Life Sci. 2004 Sep;61(18):2322-31
15378203
Clin Immunol. 2009 Jan;130(1):51-60
18835224
Infect Immun. 2001 Jun;69(6):3980-8
11349067
J Exp Med. 2006 Jul 10;203(7):1623-8
16785311
Nat Immunol. 2005 Aug;6(8):844-51
16025117
Infect Immun. 2000 Jan;68(1):46-53
10603367
Infect Immun. 1993 Sep;61(9):3981-4
8359920
Neurogastroenterol Motil. 2009 Jan;21(1):6-17
19140954
Mol Med. 2003 May-Aug;9(5-8):125-34
14571320
Mini Rev Med Chem. 2008 Nov;8(13):1328-42
18991751
J Appl Toxicol. 2006 May-Jun;26(3):262-8
16583462
J Appl Toxicol. 2007 Sep-Oct;27(5):482-90
17309042
Nat Med. 2004 Nov;10(11):1216-21
15502843
Gastroenterology. 2006 May;130(6):1822-30
16697744
Crit Care Med. 2008 Feb;36(2):404-8
18091537
J Immunol. 2006 Jan 1;176(1):496-506
16365443
Eur J Pharmacol. 2007 Jan 26;555(2-3):122-8
17113068
Curr Med Chem. 2008;15(8):743-53
18393843
Life Sci. 2007 May 30;80(24-25):2325-9
17289087
Proc Natl Acad Sci U S A. 1986 Jul;83(14):5189-93
3523484
Int J Immunopathol Pharmacol. 2008 Oct-Dec;21(4):891-901
19144274
Semin Immunol. 2006 Dec;18(6):347-61
16997570
Drug Metab Dispos. 1983 Jul-Aug;11(4):366-70
6137345
J Clin Invest. 2007 Feb;117(2):289-96
17273548
Nature. 2002 Dec 19-26;420(6917):853-9
12490958
J Infect Dis. 1984 Sep;150(3):425-35
6207248
J Infect Dis. 2005 Jun 15;191(12):2138-48
15898001
J Appl Toxicol. 2005 Jan-Feb;25(1):68-73
15669039
J Endotoxin Res. 2005;11(6):395-9
16303097
Cochrane Database Syst Rev. 2005 Jan 25;(1):CD005085
15654704
Eur J Immunol. 1995 Aug;25(8):2220-7
7664785
J Exp Med. 1997 Aug 18;186(4):569-80
9254655
Langenbecks Arch Surg. 2006 Apr;391(2):83-7
16568325
Mol Immunol. 2003 Mar;39(13):763-70
12617991
World J Surg. 2005 Nov;29(11):1483-9
16222449
Infect Immun. 2007 Dec;75(12):5753-62
17875635
J Appl Toxicol. 1998 Jul-Aug;18(4):293-8
9719430
Microbes Infect. 2004 Apr;6(4):398-405
15101397
Crit Care Med. 2006 Feb;34(2):502-10
16424734
Infect Immun. 1992 Mar;60(3):791-7
1541553
Gastroenterology. 2006 Oct;131(4):1122-30
17030182
Nature. 2000 May 25;405(6785):458-62
10839541
Clin Chim Acta. 1961 Jul;6:538-44
14453500