title: TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection.
abstract: Calcium signaling in phagocytes is essential for cellular activation, migration, and the potential resolution of infection or inflammation. The generation of reactive oxygen species (ROS) via activation of NADPH (nicotinamide adenine dinucleotide phosphate)-oxidase activity in macrophages has been linked to altered intracellular calcium concentrations. Because of its role as an oxidative stress sensor in phagocytes, we investigated the function of the cation channel transient receptor potential melastatin 2 (TRPM2) in macrophages during oxidative stress responses induced by Helicobacter pylori infection. We show that Trpm2-/-mice, when chronically infected with H. pylori, exhibit increased gastric inflammation and decreased bacterial colonization compared with wild-type (WT) mice. The absence of TRPM2 triggers greater macrophage production of inflammatory mediators and promotes classically activated macrophage M1 polarization in response to H. pylori. TRPM2-deficient macrophages upon H. pylori stimulation are unable to control intracellular calcium levels, which results in calcium overloading. Furthermore, increased intracellular calcium in TRPM2-/-macrophages enhanced mitogen-activated protein kinase and NADPH-oxidase activities, compared with WT macrophages. Our data suggest that augmented production of ROS and inflammatory cytokines with TRPM2 deletion regulates oxidative stress in macrophages and consequently decreases H. pylori gastric colonization while increasing inflammation in the gastric mucosa.
authors.affiliation: Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Beceiro
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Radin
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chatuvedi
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Horvarth
authors.affiliation: Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cortado
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dixon
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: C
authors.initials: C
authors.lastname: Gu
authors.affiliation: The Daniel K Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii, USA.
authors.forename: I
authors.initials: I
authors.lastname: Lange
authors.affiliation: The Daniel K Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii, USA.
authors.forename: D-Lt
authors.initials: DL
authors.lastname: Koomoa
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.|Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.|Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: H M S
authors.initials: HM
authors.lastname: Algood
authors.affiliation: Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.|Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Partida-Sánchez
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005756:Gastritis / Q000235:genetics* / Q000276:immunology; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D009249:NADP