title: Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori.
abstract: Helicobacter pylori incites a futile inflammatory response, which is the key feature of its immunopathogenesis. This leads to the ability of this bacterial pathogen to survive in the stomach and cause peptic ulcers and gastric cancer. Myeloid cells recruited to the gastric mucosa during H. pylori infection have been directly implicated in the modulation of host defense against the bacterium and gastric inflammation. Heme oxygenase-1 (HO-1) is an inducible enzyme that exhibits anti-inflammatory functions. Our aim was to analyze the induction and role of HO-1 in macrophages during H. pylori infection. We now show that phosphorylation of the H. pylori virulence factor cytotoxin-associated gene A (CagA) in macrophages results in expression of hmox-1, the gene encoding HO-1, through p38/NF (erythroid-derived 2)-like 2 signaling. Blocking phagocytosis prevented CagA phosphorylation and HO-1 induction. The expression of HO-1 was also increased in gastric mononuclear cells of human patients and macrophages of mice infected with cagA(+) H. pylori strains. Genetic ablation of hmox-1 in H. pylori-infected mice increased histologic gastritis, which was associated with enhanced M1/Th1/Th17 responses, decreased regulatory macrophage (Mreg) response, and reduced H. pylori colonization. Gastric macrophages of H. pylori-infected mice and macrophages infected in vitro with this bacterium showed an M1/Mreg mixed polarization type; deletion of hmox-1 or inhibition of HO-1 in macrophages caused an increased M1 and a decrease of Mreg phenotype. These data highlight a mechanism by which H. pylori impairs the immune response and favors its own survival via activation of macrophage HO-1.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Institut National de la Recherche Agronomique, Unité de Recherche Microbiologie (UR454), 63122 Saint-Genès-Champanelle, France;
authors.forename: Alain P
authors.initials: AP
authors.lastname: Gobert
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Thomas
authors.initials: T
authors.lastname: Verriere
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Barry
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Thibaut
authors.initials: T
authors.lastname: de Sablet
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Alberto G
authors.initials: AG
authors.lastname: Delgado
authors.affiliation: Departamento de Patología, Escuela de Medicina, Universidad del Valle, Cali, Colombia;
authors.forename: Luis E
authors.initials: LE
authors.lastname: Bravo
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212; and.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212; and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232 keith.wilson@vanderbilt.edu.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005753:Gastric Mucosa / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D005756:Gastritis / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000276:immunology* / Q000472:pathogenicity; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010587:Phagocytosis / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013270:Stomach / Q000382:microbiology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C556062:IL10 protein, mouse; D007093:Imidazoles; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011725:Pyridines; C080866:cagA protein, Helicobacter pylori; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
references.citation: J Immunol. 2011 Nov 15;187(10):5370-9
references.pmid: 21987660
references.citation: Infect Immun. 2005 Jul;73(7):4180-9
references.pmid: 15972508
references.citation: Infect Immun. 1995 Apr;63(4):1183-7
references.pmid: 7890370
references.citation: Nat Rev Immunol. 2008 Dec;8(12):958-69
references.pmid: 19029990
references.citation: J Immunol. 2008 Apr 1;180(7):5017-27
references.pmid: 18354227
references.citation: Nat Med. 2002 Mar;8(3):240-6
references.pmid: 11875494
references.citation: Hum Gene Ther. 2001 May 20;12(8):967-79
references.pmid: 11387061
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14648-53
references.pmid: 8962108
references.citation: J Immunol. 1999 Nov 15;163(10):5552-9
references.pmid: 10553083
references.citation: J Biol Chem. 2004 Apr 23;279(17):17205-16
references.pmid: 14963045
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7595-9
references.pmid: 9207137
references.citation: J Immunol. 2006 Dec 1;177(11):7950-8
references.pmid: 17114467
references.citation: Gastroenterology. 1998 Mar;114(3):482-92
references.pmid: 9496938
references.citation: Gut. 2011 Sep;60(9):1189-95
references.pmid: 21357593
references.citation: J Leukoc Biol. 2006 Dec;80(6):1298-307
references.pmid: 16905575
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16986-91
references.pmid: 23033494
references.citation: J Clin Invest. 2012 Apr;122(4):1553-66
references.pmid: 22378042
references.citation: Gastroenterology. 2011 Jan;140(1):199-209
references.pmid: 20600031
references.citation: Infect Immun. 2012 Aug;80(8):2724-34
references.pmid: 22615251
references.citation: J Immunol. 2002 Jun 15;168(12):6002-6
references.pmid: 12055207
references.citation: J Leukoc Biol. 2012 May;91(5):685-99
references.pmid: 22416259
references.citation: Gastroenterology. 2010 Mar;138(3):1046-54
references.pmid: 19931266
references.citation: Cell Microbiol. 2001 Jan;3(1):21-31
references.pmid: 11207617
references.citation: Infect Immun. 2008 May;76(5):2235-9
references.pmid: 18332213
references.citation: Gastroenterology. 2008 Jul;135(1):91-9
references.pmid: 18474244
references.citation: Science. 2003 May 30;300(5624):1430-4
references.pmid: 12775840
references.citation: J Immunol. 2004 Sep 1;173(5):3467-81
references.pmid: 15322212
references.citation: Infect Immun. 2007 Sep;75(9):4305-15
references.pmid: 17562760
references.citation: Gastroenterology. 2007 Jul;133(1):288-308
references.pmid: 17631150
references.citation: J Clin Invest. 2012 Jul;122(7):2531-42
references.pmid: 22728935
references.citation: J Leukoc Biol. 2002 Jul;72(1):101-6
references.pmid: 12101268
references.citation: Science. 2003 Sep 12;301(5639):1527-30
references.pmid: 12970564
references.citation: Mol Microbiol. 2001 Nov;42(3):631-44
references.pmid: 11722731
references.citation: PLoS One. 2010 Nov 23;5(11):e15018
references.pmid: 21124899
references.citation: Cell Microbiol. 2013 Jan;15(1):145-56
references.pmid: 23051580
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919-24
references.pmid: 9380735
references.citation: Gastroenterology. 2007 Jul;133(1):150-163.e3
references.pmid: 17631139
references.citation: J Biol Chem. 2004 Jan 2;279(1):245-50
references.pmid: 14573621
references.citation: Biochem J. 2002 Nov 15;368(Pt 1):121-9
references.pmid: 12150710
references.citation: Lab Invest. 2008 Jun;88(6):664-81
references.pmid: 18475258
references.citation: J Immunol. 2008 Jan 15;180(2):1207-16
references.pmid: 18178861
references.citation: Am J Respir Cell Mol Biol. 1995 Oct;13(4):387-98
references.pmid: 7546768
references.citation: Immunol Cell Biol. 2009 Mar-Apr;87(3):235-40
references.pmid: 19104504
references.citation: J Exp Med. 2005 Mar 7;201(5):747-54
references.pmid: 15753208
references.citation: J Immunol. 2009 Dec 15;183(12):8099-109
references.pmid: 20007577
references.citation: Immunobiology. 2010 Sep-Oct;215(9-10):788-95
references.pmid: 20580464
references.citation: Infect Immun. 2005 Dec;73(12):8322-33
references.pmid: 16299330
references.citation: Science. 2000 Feb 25;287(5457):1497-500
references.pmid: 10688800
references.citation: Cell Host Microbe. 2008 May 15;3(5):323-30
references.pmid: 18474359
references.citation: J Immunol. 2010 May 1;184(9):5121-9
references.pmid: 20351183
references.citation: Infect Immun. 2004 May;72(5):2889-98
references.pmid: 15102801
references.citation: Physiol Rev. 2006 Apr;86(2):583-650
references.pmid: 16601269
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13844-9
references.pmid: 11717441
references.citation: Am J Physiol Renal Physiol. 2000 May;278(5):F726-36
references.pmid: 10807584
references.citation: Gastroenterology. 2010 Nov;139(5):1686-98, 1698.e1-6
references.pmid: 20600019
references.citation: Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2100-5
references.pmid: 16123320
references.citation: J Biol Chem. 2000 May 26;275(21):16023-9
references.pmid: 10821856
references.citation: J Immunol. 2011 Mar 15;186(6):3632-41
references.pmid: 21296975
references.citation: Cancer Res. 1999 Dec 15;59(24):6124-31
references.pmid: 10626802