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.
Copyright © 2014 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antigens, Bacterial / genetics
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Antigens, Bacterial / immunology*
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Bacterial Proteins / genetics
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Bacterial Proteins / immunology*
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Cell Line
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Enzyme Inhibitors / pharmacology
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Gastric Mucosa / cytology
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Gastric Mucosa / immunology
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Gastric Mucosa / microbiology
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Gastritis / immunology
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Gastritis / microbiology
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Helicobacter Infections / immunology*
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Helicobacter Infections / microbiology
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Helicobacter pylori / immunology*
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Helicobacter pylori / pathogenicity
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Heme Oxygenase-1 / antagonists & inhibitors
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Heme Oxygenase-1 / biosynthesis
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / immunology*
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Humans
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Imidazoles / pharmacology
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Inflammation / immunology
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Interleukin-10 / biosynthesis
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MAP Kinase Signaling System / immunology
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Macrophages / enzymology
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Macrophages / immunology*
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-E2-Related Factor 2 / immunology
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Nitric Oxide Synthase Type II / biosynthesis
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Phagocytosis / immunology
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Phosphorylation / immunology
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Pyridines / pharmacology
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Signal Transduction / immunology
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Stomach / microbiology
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Stomach / pathology
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Th1 Cells / immunology
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Th17 Cells / immunology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / immunology
Substances
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Antigens, Bacterial
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Bacterial Proteins
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Enzyme Inhibitors
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IL10 protein, mouse
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Imidazoles
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Membrane Proteins
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Pyridines
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cagA protein, Helicobacter pylori
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Interleukin-10
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Heme Oxygenase-1
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Hmox1 protein, mouse
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p38 Mitogen-Activated Protein Kinases
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SB 203580