Immune Evasion byHelicobacter pyloriIs Mediated by Induction of Macrophage Arginase II

Abstract

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.

Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications

“…H. pylori PMSS1 and SS1 were cultured as previously described (25,42). PMSS1 was used for acute in vivo and ex vivo infections because it is the original clinical isolate and retains its ability to translocate the oncoprotein, CagA.…”

“…Male mice were selected because previous studies have demonstrated that female mice are protected from gastric damage during H. pylori infection (60). Sample sizes were based on previous studies (14,25,42,61). No other selection criteria were used in these studies.…”

“…Δmye , and LysM cre/cre mice were investigated for their response to infection with H. pylori SS1 for 4 mo, a model of chronic H. pylori infection (14,25,42). Odc Δmye mice demonstrated significantly enhanced acute and chronic histologic gastritis, compared with either Odc fl/fl or LysM cre/cre mice (Fig.…”

Polyamines and transglutaminases: future perspectives

“…This study used clustered charged-to-alanine mutagenesis and structural modeling to address this question, and generated four new mutants of yeast eIF5A. Chaturvedi et al (2012) who previously reported the importance of utilizing l-arginine as a host response to the gastric pathogen Helicobacter pylori, now show that generation of antimicrobial nitric oxide (NO) by inducible NO synthase (iNOS), which is dependent on l-arginine availability, is limited by competition with arginase II activity (Lewis et al 2011) and upregulation of ODC. Spermine blocks l-arginine uptake into macrophages (Chaturvedi et al 2010) and SMO mediates DNA damage in gastric epithelial cells.…”

Role of polyamines, their analogs and transglutaminases in biological and clinical perspectives

“…The authors show that generation of antimicrobial nitric oxide (NO) by inducible NO synthase (iNOS), which is dependent on L-arginine availability, is limited by competition with arginase II activity (Lewis et al 2011) and upregulation of ornithine decarboxylase. Spermine blocks L-arginine uptake into macrophages (Chaturvedi et al 2010) and SMO mediates DNA damage in gastric epithelial cells.…”