Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II.

Lewis ND, Asim M, Barry DP, de Sablet T, Singh K, Piazuelo MB, Gobert AP, Chaturvedi R, Wilson KT
J Immunol. 2011 186 (6): 3632-41

PMID: 21296975 · PMCID: PMC3069806 · DOI:10.4049/jimmunol.1003431

Helicobacter pylori infection persists for the life of the host due to the failure of the immune response to eradicate the bacterium. Determining how H. pylori escapes the immune response in its gastric niche is clinically important. We have demonstrated in vitro that macrophage NO production can kill H. pylori, but induction of macrophage arginase II (Arg2) inhibits inducible NO synthase (iNOS) translation, causes apoptosis, and restricts bacterial killing. Using a chronic H. pylori infection model, we determined whether Arg2 impairs host defense in vivo. In C57BL/6 mice, expression of Arg2, but not arginase I, was abundant and localized to gastric macrophages. Arg2(-/-) mice had increased histologic gastritis and decreased bacterial colonization compared with wild-type (WT) mice. Increased gastritis scores correlated with decreased colonization in individual Arg2(-/-) mice but not in WT mice. When mice infected with H. pylori were compared, Arg2(-/-) mice had more gastric macrophages, more of these cells were iNOS(+), and these cells expressed higher levels of iNOS protein, as determined by flow cytometry and immunofluorescence microscopy. There was enhanced nitrotyrosine staining in infected Arg2(-/-) versus WT mice, indicating increased NO generation. Infected Arg2(-/-) mice exhibited decreased macrophage apoptosis, as well as enhanced IFN-γ, IL-17a, and IL-12p40 expression, and reduced IL-10 levels consistent with a more vigorous Th1/Th17 response. These studies demonstrate that Arg2 contributes to the immune evasion of H. pylori by limiting macrophage iNOS protein expression and NO production, mediating macrophage apoptosis, and restraining proinflammatory cytokine responses.

MeSH Terms (14)

Animals Arginase Disease Models, Animal Enzyme Induction Helicobacter Infections Helicobacter pylori Immune Evasion Intestinal Mucosa Macrophages Male Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Synthase Type II

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