title: Helicobacter pylori-induced IL-1β secretion in innate immune cells is regulated by the NLRP3 inflammasome and requires the cag pathogenicity island.
abstract: Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world's population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1β production have been associated with increased risk for gastric cancer. To be active, pro-IL-1β must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow-derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1β upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori-induced IL-1β secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain-containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany;
authors.forename: Raphaela P
authors.initials: RP
authors.lastname: Semper
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany;
authors.forename: Raquel
authors.initials: R
authors.lastname: Mejías-Luque
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;
authors.forename: Christina
authors.initials: C
authors.lastname: Groß
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Anderl
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland;
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
authors.affiliation: Institut für Pathologie, Klinikum Bayreuth, 95445 Bayreuth, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany; German Centre for Infection Research, Partner Site Munich, 81675 Munich, Germany.
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany;
authors.forename: Clarissa
authors.initials: C
authors.lastname: Prazeres da Costa
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany; German Centre for Infection Research, Partner Site Munich, 81675 Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany;
authors.forename: Olaf
authors.initials: O
authors.lastname: Groß
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany; German Centre for Infection Research, Partner Site Munich, 81675 Munich, Germany markus.gerhard@tum.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Gerhard
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D005260:Female; D044404:Genomic Islands / Q000235:genetics / Q000276:immunology*; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D008297:Male; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C074689:VacA protein, Helicobacter pylori