Keith Wilson
Faculty Member
Last active: 11/2/2019

Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori.

Gobert AP, Verriere T, Asim M, Barry DP, Piazuelo MB, de Sablet T, Delgado AG, Bravo LE, Correa P, Peek RM, Chaturvedi R, Wilson KT
J Immunol. 2014 193 (6): 3013-22

PMID: 25108023 · PMCID: PMC4171064 · DOI:10.4049/jimmunol.1401075

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.

MeSH Terms (30)

Animals Antigens, Bacterial Bacterial Proteins Cell Line Enzyme Inhibitors Gastric Mucosa Gastritis Helicobacter Infections Helicobacter pylori Heme Oxygenase-1 Humans Imidazoles Inflammation Interleukin-10 Macrophages MAP Kinase Signaling System Membrane Proteins Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2 Nitric Oxide Synthase Type II p38 Mitogen-Activated Protein Kinases Phagocytosis Phosphorylation Pyridines Signal Transduction Stomach Th1 Cells Th17 Cells

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