title: Arginase 2 deletion leads to enhanced M1 macrophage activation and upregulated polyamine metabolism in response to Helicobacter pylori infection.
abstract: We reported that arginase 2 (ARG2) deletion results in increased gastritis and decreased bacterial burden during Helicobacter pylori infection in mice. Our studies implicated a potential role for inducible nitric oxide (NO) synthase (NOS2), as Arg2 (-/-) mice exhibited increased NOS2 levels in gastric macrophages, and NO can kill H. pylori. We now bred Arg2 (-/-) to Nos2 (-/-) mice, and infected them with H. pylori. Compared to wild-type mice, both Arg2 (-/-) and Arg2 (-/-) ;Nos2 (-/-) mice exhibited increased gastritis and decreased colonization, the latter indicating that the effect of ARG2 deletion on bacterial burden was not mediated by NO. While Arg2 (-/-) mice demonstrated enhanced M1 macrophage activation, Nos2 (-/-) and Arg2 (-/-) ;Nos2 (-/-) mice did not demonstrate these changes, but exhibited increased CXCL1 and CXCL2 responses. There was an increased expression of the Th1/Th17 cytokines, interferon gamma and interleukin 17, in gastric tissues and splenic T-cells from Arg2 (-/-), but not Nos2 (-/-) or Arg2 (-/-) ;Nos2 (-/-) mice. Gastric tissues from infected Arg2 (-/-) mice demonstrated increased expression of arginase 1, ornithine decarboxylase, adenosylmethionine decarboxylase 1, spermidine/spermine N (1)-acetyltransferase 1, and spermine oxidase, along with increased spermine levels. These data indicate that ARG2 deletion results in compensatory upregulation of gastric polyamine synthesis and catabolism during H. pylori infection, which may contribute to increased gastric inflammation and associated decreased bacterial load. Overall, the finding of this study is that ARG2 contributes to the immune evasion of H. pylori by restricting M1 macrophage activation and polyamine metabolism.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, 2215 Garland Avenue, 1030C Medical Research Building IV, Nashville, TN, 37232, USA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Hardbower
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.affiliation: The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Murray-Stewart
authors.affiliation: The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Verriere
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Nuruddeen D
authors.initials: ND
authors.lastname: Lewis
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, 2215 Garland Avenue, 1030C Medical Research Building IV, Nashville, TN, 37232, USA. keith.wilson@vanderbilt.edu.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. keith.wilson@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. keith.wilson@vanderbilt.edu.|Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA. keith.wilson@vanderbilt.edu.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA. keith.wilson@vanderbilt.edu.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology*; D015317:Biogenic Polyamines / Q000276:immunology*; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016480:Helicobacter pylori / Q000378:metabolism*; D057131:Immune Evasion; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D013270:Stomach / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D015317:Biogenic Polyamines; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C481673:Arg2 protein, mouse; D001119:Arginase
keywords: Helicobacter pylori; Immune evasion; Macrophage activation; Polyamines