title: Noradrenergic neurons regulate monocyte trafficking and mortality during gram-negative peritonitis in mice.
abstract: Effective host defense requires a robust, yet self-limited response to pathogens. A poorly calibrated response can lead to either bacterial dissemination due to insufficient inflammation or organ injury due to excessive inflammation. Recent evidence suggests that the cholinergic anti-inflammatory reflex helps calibrate the immune response. However, the influence of peripheral noradrenergic neurons, which are primarily sympathetic neurons, in regulating immunity remains incompletely characterized. Using a model of 6-hydroxydopamine-mediated noradrenergic nerve ablation, we show that elimination of noradrenergic neurons improves survival during Klebsiella pneumoniae peritonitis (67 versus 23%, p < 0.005) in mice. The survival benefit results from enhanced MCP-1-dependent monocyte recruitment and a subsequent decrease in bacterial loads. Splenectomy eliminated both the survival benefit of 6-hydroxydopamine and monocyte recruitment, suggesting that monocytes recruited to the peritoneum originate in the spleen. These results suggest that noradrenergic neurons regulate the immune response through two pathways. First, sympathetic nerve-derived norepinephrine directly restrains MCP-1 production by peritoneal macrophages during infection. Second, norepinephrine derived from the vagally innervated splenic nerve regulates splenic monocyte egress. Removal of these two modulators of the immune response enhances antibacterial immunity and improves survival. These results may have implications for how states of catecholamine excess influence the host response to bacterial infections.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. eric.seeley@ucsf.edu
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Seeley
authors.forename: Sophia S
authors.initials: SS
authors.lastname: Barry
authors.forename: Saisindhu
authors.initials: S
authors.lastname: Narala
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
mesh_terms: D059331:Adrenergic Neurons / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007710:Klebsiella Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D010538:Peritonitis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines
references.citation: J Exp Med. 2012 Jun 4;209(6):1057-68
references.pmid: 22665702
references.citation: Science. 2011 Oct 7;334(6052):101-5
references.pmid: 21921158
references.citation: J Exp Med. 2012 Jan 16;209(1):123-37
references.pmid: 22213805
references.citation: J Immunol. 1994 Mar 15;152(6):3024-31
references.pmid: 8144901
references.citation: Nat Med. 2004 Nov;10(11):1216-21
references.pmid: 15502843
references.citation: Dev Comp Immunol. 2011 Jun;35(6):685-91
references.pmid: 21295067
references.citation: J Immunol. 2010 Dec 1;185(11):6930-8
references.pmid: 21041722
references.citation: Science. 2011 May 6;332(6030):729-32
references.pmid: 21474712
references.citation: Pharmacol Rev. 1974 Sep;26(3):199-288
references.pmid: 4376244
references.citation: Science. 2009 Jul 31;325(5940):612-6
references.pmid: 19644120
references.citation: Mol Cell Biol. 2000 Jun;20(11):4106-14
references.pmid: 10805752
references.citation: Crit Care Med. 2007 Apr;35(4):1139-44
references.pmid: 17334244
references.citation: Nature. 2000 May 25;405(6785):458-62
references.pmid: 10839541
references.citation: Clin Exp Pharmacol Physiol. 2006 Aug;33(8):746-50
references.pmid: 16895550
references.citation: Brain Behav Immun. 2011 Nov;25(8):1708-15
references.pmid: 21767631
references.citation: J Leukoc Biol. 2009 Dec;86(6):1269-70
references.pmid: 19948519
references.citation: Nature. 2007 Oct 11;449(7163):721-5
references.pmid: 17914358
references.citation: Science. 2011 Oct 7;334(6052):98-101
references.pmid: 21921156
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11008-13
references.pmid: 18669662
references.citation: J Immunol. 2010 Jan 15;184(2):540-4
references.pmid: 20018617
references.citation: FASEB J. 2011 Dec;25(12):4476-85
references.pmid: 21840939
references.citation: J Exp Med. 2006 Jul 10;203(7):1623-8
references.pmid: 16785311
references.citation: J Immunol. 2008 Oct 15;181(8):5598-605
references.pmid: 18832718
references.citation: FASEB J. 2012 May;26(5):2137-44
references.pmid: 22318967
references.citation: J Leukoc Biol. 1997 Feb;61(2):156-60
references.pmid: 9021920
references.citation: J Exp Med. 2005 Apr 4;201(7):1113-23
references.pmid: 15809354
references.citation: Ann Surg. 2001 Feb;233(2):266-75
references.pmid: 11176134
references.citation: J Infect Dis. 2005 Aug 15;192(4):560-72
references.pmid: 16028124
references.citation: N Engl J Med. 1991 Feb 14;324(7):429-36
references.pmid: 1988827
references.citation: J Infect Dis. 2005 Jun 15;191(12):2138-48
references.pmid: 15898001
references.citation: Ann N Y Acad Sci. 1998 May 1;840:262-8
references.pmid: 9629254
references.citation: N Engl J Med. 1987 Sep 10;317(11):653-8
references.pmid: 3306374
references.citation: Dev Comp Immunol. 2008;32(6):627-36
references.pmid: 17988735
references.citation: PLoS One. 2009;4(2):e4414
references.pmid: 19212441
references.citation: N Engl J Med. 2003 Apr 17;348(16):1546-54
references.pmid: 12700374
references.citation: J Immunol. 2011 Apr 1;186(7):4340-6
references.pmid: 21339364
references.citation: J Clin Invest. 1996 Feb 1;97(3):713-9
references.pmid: 8609227
references.citation: Arthritis Rheum. 2005 Apr;52(4):1305-13
references.pmid: 15818682
references.citation: Nat Rev Immunol. 2009 Jun;9(6):418-28
references.pmid: 19461672
references.citation: J Infect Dis. 2008 Sep 1;198(5):750-7
references.pmid: 18627272