title: The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity.
abstract: The indigenous microbiota impact mucosal, as well as systemic, immune responses, but whether the microbiota are involved in stressor-induced immunomodulation has not been thoroughly tested. A well characterized murine stressor, called social disruption (SDR), was used to study whether the microbiota are involved in stressor-induced enhancement of macrophage reactivity. Exposure to the SDR Stressor enhanced the ability of splenic macrophages to produce microbicidal mediators (e.g., inducible nitric oxide synthase (iNOS), superoxide anion, and peroxynitrite) and to kill target Escherichia coli. Exposure to the SDR Stressor also increased cytokine production by LPS-stimulated splenic macrophages. These effects, however, were impacted by the microbiota. Microbicidal activity and cytokine mRNA in splenic macrophages from Swiss Webster germfree mice that lack any commensal microbiota were not enhanced by exposure to the SDR Stressor. However, when germfree mice were conventionalized by colonizing them with microbiota from CD1 conventional donor mice, exposure to the SDR Stressor again increased microbicidal activity and cytokine mRNA. In follow-up experiments, immunocompetent conventional CD1 mice were treated with a cocktail of antibiotics to disrupt the intestinal microbiota. While exposure to the SDR Stressor-enhanced splenic macrophage microbicidal activity and cytokine production in vehicle-treated mice, treatment with antibiotics attenuated the SDR Stressor-induced increases in splenic macrophage reactivity. Treatment with antibiotics also prevented the stressor-induced increase in circulating levels of bacterial peptidoglycan, suggesting that translocation of microbiota-derived peptidoglycan into the body primes the innate immune system for enhanced activity. This study demonstrates that the microbiota play a crucial role in stressor-induced immunoenhancement.
authors.affiliation: Integrated Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Allen
authors.forename: William P
authors.initials: WP
authors.lastname: Lafuse
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Galley
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Ali
authors.forename: Brian M M
authors.initials: BM
authors.lastname: Ahmer
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bailey
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology*; D004926:Escherichia coli; D018928:Immunity, Mucosal; D056747:Immunomodulation; D007422:Intestines / Q000276:immunology* / Q000382:microbiology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D054892:Metagenome / Q000276:immunology*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D030421:Peroxynitrous Acid / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013315:Stress, Psychological / Q000276:immunology*; D013481:Superoxides / Q000276:immunology
chemical_list: D016207:Cytokines; D013481:Superoxides; D030421:Peroxynitrous Acid; D052247:Nitric Oxide Synthase Type II
references.citation: J Immunol. 2009 Jun 15;182(12):7888-96
references.pmid: 19494313
references.citation: Neuroscience. 2005;135(4):1295-307
references.pmid: 16165282
references.citation: J Neuroimmunol. 2004 Mar;148(1-2):106-15
references.pmid: 14975591
references.citation: Drugs. 2010 Jun 18;70(9):1131-48
references.pmid: 20518580
references.citation: FEMS Immunol Med Microbiol. 1996 Sep;15(2-3):129-34
references.pmid: 8880138
references.citation: Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R422-32
references.pmid: 12399247
references.citation: Adv Exp Med Biol. 1999;473:11-30
references.pmid: 10659341
references.citation: Brain Behav Immun. 2002 Aug;16(4):461-76
references.pmid: 12096891
references.citation: Am J Physiol. 1998 Sep;275(3):R870-8
references.pmid: 9728086
references.citation: Cell. 2004 Jul 23;118(2):229-41
references.pmid: 15260992
references.citation: EMBO Rep. 2006 Jul;7(7):688-93
references.pmid: 16819463
references.citation: Psychoneuroendocrinology. 2008 Jan;33(1):108-17
references.pmid: 18037570
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1180-90
references.pmid: 17596326
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G198-203
references.pmid: 17510196
references.citation: J Immunol Methods. 1996 Oct 16;197(1-2):139-50
references.pmid: 8890901
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105 Suppl 1:11512-9
references.pmid: 18695234
references.citation: Brain Behav Immun. 2005 Jul;19(4):311-7
references.pmid: 15944070
references.citation: Clin Dermatol. 2000 May-Jun;18(3):369-73
references.pmid: 10856669
references.citation: J Biol Chem. 2010 Jul 2;285(27):20724-31
references.pmid: 20427277
references.citation: Mayo Clin Proc. 1999 Sep;74(9):928-35
references.pmid: 10488798
references.citation: Physiol Behav. 2002 Nov;77(2-3):291-9
references.pmid: 12419405
references.citation: J Neuroimmunol. 2006 Feb;171(1-2):29-37
references.pmid: 16253348
references.citation: J Biol Chem. 2004 Jun 25;279(26):27059-68
references.pmid: 15102856
references.citation: Semin Immunopathol. 2008 Jul;30(3):279-89
references.pmid: 18536919
references.citation: Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
references.pmid: 8944624
references.citation: J Immunol. 2009 Nov 15;183(10):6041-50
references.pmid: 19841183
references.citation: Infect Immun. 2009 Jun;77(6):2367-75
references.pmid: 19307217
references.citation: Gut. 2011 Mar;60(3):307-17
references.pmid: 20966022
references.citation: Cell. 1994 Sep 23;78(6):915-8
references.pmid: 7522969
references.citation: Ann N Y Acad Sci. 2004 Dec;1029:36-43
references.pmid: 15681741
references.citation: PLoS Biol. 2008 Nov 18;6(11):e280
references.pmid: 19018661
references.citation: Cell Signal. 2001 Feb;13(2):85-94
references.pmid: 11257452
references.citation: Physiol Behav. 2009 Sep 7;98(3):351-8
references.pmid: 19560480
references.citation: Trends Immunol. 2003 Aug;24(8):444-8
references.pmid: 12909458
references.citation: Dig Dis Sci. 2002 Jan;47(1):208-15
references.pmid: 11852879
references.citation: J Neuroimmunol. 2002 Mar;124(1-2):9-15
references.pmid: 11958817
references.citation: Neuro Endocrinol Lett. 2008 Jun;29(3):287-91
references.pmid: 18580840
references.citation: Brain Behav Immun. 2011 Mar;25(3):397-407
references.pmid: 21040780
references.citation: Infect Immun. 2003 Jan;71(1):22-9
references.pmid: 12496145
references.citation: J Biol Chem. 2004 Dec 10;279(50):51715-8
references.pmid: 15364933
references.citation: Infect Immun. 2010 Apr;78(4):1509-19
references.pmid: 20145094
references.citation: Gastroenterology. 2011 Aug;141(2):599-609, 609.e1-3
references.pmid: 21683077
references.citation: Nat Med. 2010 Feb;16(2):228-31
references.pmid: 20081863
references.citation: Neuro Endocrinol Lett. 2008 Feb;29(1):117-24
references.pmid: 18283240
references.citation: J Clin Microbiol. 1991 Nov;29(11):2477-83
references.pmid: 1774252
references.citation: Nat Rev Immunol. 2004 Mar;4(3):181-9
references.pmid: 15039755
references.citation: Am J Physiol Regul Integr Comp Physiol. 2001 Jun;280(6):R1799-805
references.pmid: 11353685
references.citation: Physiol Behav. 2009 Mar 23;96(4-5):557-67
references.pmid: 19135464
references.citation: Nat Rev Gastroenterol Hepatol. 2009 May;6(5):306-14
references.pmid: 19404271
references.citation: Neurogastroenterol Motil. 2011 Mar;23(3):255-64, e119
references.pmid: 21054680
references.citation: J Appl Physiol (1985). 2003 Jan;94(1):43-52
references.pmid: 12391077
references.citation: PLoS Pathog. 2010 May 27;6(5):e1000549
references.pmid: 20523892
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Dec;283(6):G1257-63
references.pmid: 12388189
references.citation: J Neuroimmunol. 2001 Apr 2;115(1-2):36-45
references.pmid: 11282152
references.citation: J Immunol. 2010 Feb 15;184(4):2014-25
references.pmid: 20083672
references.citation: Brain Res. 2003 Nov 21;991(1-2):123-32
references.pmid: 14575884