title: Myeloid HIF-1 is protective in Helicobacter pylori-mediated gastritis.
abstract: Helicobacter pylori infection triggers chronic inflammation of the gastric mucosa that may progress to gastric cancer. The hypoxia-inducible factors (HIFs) are the central mediators of cellular adaptation to low oxygen levels (hypoxia), but they have emerged recently as major transcriptional regulators of immunity and inflammation. No studies have investigated whether H. pylori affects HIF signaling in immune cells and a potential role for HIF in H. pylori-mediated gastritis. HIF-1 and HIF-2 expression was examined in human H. pylori-positive gastritis biopsies. Subsequent experiments were performed in naive and polarized bone marrow-derived macrophages from wild-type (WT) and myeloid HIF-1α-null mice (HIF-1(Δmyel)). WT and HIF-1(Δmyel) mice were inoculated with H. pylori by oral gavage and sacrificed 6 mo postinfection. HIF-1 was specifically expressed in macrophages of human H. pylori-positive gastritis biopsies. Macrophage HIF-1 strongly contributed to the induction of proinflammatory genes (IL-6, IL-1β) and inducible NO synthase in response to H. pylori. HIF-2 expression and markers of M2 macrophage differentiation were decreased in response to H. pylori. HIF-1(Δmyel) mice inoculated with H. pylori for 6 mo presented with a similar bacterial colonization than WT mice but, surprisingly, a global increase of inflammation, leading to a worsening of the gastritis, measured by an increased epithelial cell proliferation. In conclusion, myeloid HIF-1 is protective in H. pylori-mediated gastritis, pointing to the complex counterbalancing roles of innate immune and inflammatory phenotypes in driving this pathology.
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France;
authors.forename: Pavle
authors.initials: P
authors.lastname: Matak
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France;
authors.forename: Mylène
authors.initials: M
authors.lastname: Heinis
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France;
authors.forename: Jacques R R
authors.initials: JR
authors.lastname: Mathieu
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093;
authors.forename: Ross
authors.initials: R
authors.lastname: Corriden
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France;
authors.forename: Sylvain
authors.initials: S
authors.lastname: Cuvellier
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Delga
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Unité Mixte de Recherche Centre National de la Recherche Scientifique 5534, Université Claude Bernard Lyon 1, Lyon, 69622 Villeurbanne Cedex, France;
authors.forename: Rémi
authors.initials: R
authors.lastname: Mounier
authors.affiliation: Hôpital Cochin, 75014 Paris, France;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rouquette
authors.affiliation: Hôpital Cochin, 75014 Paris, France;
authors.forename: Josette
authors.initials: J
authors.lastname: Raymond
authors.affiliation: Equipe d'Accueil 4340, Université de Versailles, and Hôpital Ambroise Paré, Assistance Publique des Hôpitaux de Paris, 92104 Boulogne, France; and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lamarque
authors.affiliation: Equipe d'Accueil 4340, Université de Versailles, and Hôpital Ambroise Paré, Assistance Publique des Hôpitaux de Paris, 92104 Boulogne, France; and.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093;
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Institut Pasteur, 75015 Paris, France.
authors.forename: Eliette
authors.initials: E
authors.lastname: Touati
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; carole.peyssonnaux@inserm.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Peyssonnaux
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001706:Biopsy; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016480:Helicobacter pylori / Q000276:immunology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D051793:Hypoxia-Inducible Factor 1; D018836:Inflammation Mediators; D000099162:Endothelial PAS Domain-Containing Protein 1