title: Characterization of the Inflammasome in Human Kupffer Cells in Response to Synthetic Agonists and Pathogens.
abstract: The liver is the largest gland in the human body and functions as an innate immune organ. Liver macrophages called Kupffer cells (KC) constitute the largest group of macrophages in the human body. Innate immune responses involving KC represent the first line of defense against pathogens in the liver. Human monocyte-derived macrophages have been used to characterize inflammasome responses that lead to the release of the proinflammatory cytokines IL-1β and IL-18, but it has not yet been determined whether human KC contain functional inflammasomes. We show, to our knowledge for the first time, that KC express genes and proteins that make up several different inflammasome complexes. Moreover, activation of KC in response to the absent in melanoma 2 (AIM2) inflammasome led to the production of IL-1β and IL-18, which activated IL-8 transcription and hepatic NK cell activity, respectively. Other inflammasome responses were also activated in response to selected bacteria and viruses. However, hepatitis B virus inhibited the AIM2 inflammasome by reducing the mRNA stability of IFN regulatory factor 7, which regulated AIM2 transcription. These data demonstrate the production of IL-1β and IL-18 in KC, suggesting that KC contain functional inflammasomes that could be important players in the innate immune response following certain infections of the liver. We think our findings could potentially aid therapeutic approaches against chronic liver diseases that activate the inflammasome.
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Claudia
authors.initials: C
authors.lastname: Zannetti
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Roblot
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Emily
authors.initials: E
authors.lastname: Charrier
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Michelle
authors.identifier: 0000-0002-6928-932X
authors.initials: M
authors.lastname: Ainouze
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Issam
authors.identifier: 0000-0002-1019-3489
authors.initials: I
authors.lastname: Tout
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: François
authors.initials: F
authors.lastname: Briat
authors.affiliation: Centre de Recherche en Cancérologie-Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon 69008, France;
authors.forename: Nathalie
authors.identifier: 0000-0002-6053-7139
authors.initials: N
authors.lastname: Isorce
authors.affiliation: Centre de Recherche en Cancérologie-Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon 69008, France;
authors.forename: Suzanne
authors.initials: S
authors.lastname: Faure-Dupuy
authors.affiliation: Centre de Recherche en Cancérologie-Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon 69008, France;
authors.forename: Maud
authors.initials: M
authors.lastname: Michelet
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Marie
authors.identifier: 0000-0002-1618-7602
authors.initials: M
authors.lastname: Marotel
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover 30625, Germany; and.
authors.forename: Semra
authors.identifier: 0000-0003-4606-8441
authors.initials: S
authors.lastname: Kati
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover 30625, Germany; and.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
authors.affiliation: Centre de Recherche en Cancérologie-Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon 69008, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Rivoire
authors.affiliation: Hospices Civils Lyon Sud, Pierre-Bénite 69310, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Traverse-Glehen
authors.affiliation: Centre de Recherche en Cancérologie-Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon 69008, France;
authors.forename: Souphalone
authors.identifier: 0000-0002-8570-1679
authors.initials: S
authors.lastname: Luangsay
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Omran
authors.identifier: 0000-0002-2539-972X
authors.initials: O
authors.lastname: Alatiff
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Thomas
authors.identifier: 0000-0002-0687-8565
authors.initials: T
authors.lastname: Henry
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
authors.affiliation: Centre de Recherche en Cancérologie-Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon 69008, France;
authors.forename: David
authors.identifier: 0000-0002-9226-3419
authors.initials: D
authors.lastname: Durantel
authors.affiliation: Centre International de Recherche en Infectiologie, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France; uzma.hasan@inserm.fr.
authors.forename: Uzma
authors.initials: U
authors.lastname: Hasan
mesh_terms: D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000276:immunology*; D008213:Lymphocyte Activation
chemical_list: C410167:AIM2 protein, human; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D058847:Inflammasomes; D050839:Interferon Regulatory Factor-7; D020382:Interleukin-18; D053583:Interleukin-1beta; D016209:Interleukin-8