title: RIPK1 protects hepatocytes from Kupffer cells-mediated TNF-induced apoptosis in mouse models of PAMP-induced hepatitis.
abstract: The severity of liver diseases is exacerbated by the death of hepatocytes, which can be induced by the sensing of pathogen associated molecular patterns (PAMPs) derived from the gut microbiota. The molecular mechanisms regulating these cell death pathways are poorly documented. In this study, we investigated the role of the receptor interacting protein kinase 1 (RIPK1), a protein known to regulate cell fate decisions, in the death of hepatocytes using two in vivo models of PAMP-induced hepatitis.
  
  
  
  Hepatitis was induced in mice by independent injections of two different bacterial PAMPs: lipopolysaccharide (LPS) and unmethylated CpG oligodeoxynucleotide (CpG-DNA) motifs. The role of RIPK1 was evaluated by using mice specifically lacking RIPK1 in liver parenchymal cells (Ripk1LPC-KO). Administration of liposome-encapsulated clodronate served to investigate the role of Kupffer cells in the establishment of the disease. Etanercept, a tumor necrosis factor (TNF)-decoy receptor, was used to study the contribution of TNF-α during LPS-mediated liver injury.
  
  
  
  Whereas RIPK1 deficiency in liver parenchymal cells did not trigger basal hepatolysis, it greatly sensitized hepatocytes to apoptosis and liver damage following a single injection of LPS or CpG-DNA. Importantly, hepatocyte death was prevented by previous macrophage depletion or by TNF inhibition.
  
  
  
  Our data highlight the pivotal function of RIPK1 in maintaining liver homeostasis in conditions of macrophage-induced TNF burst in response to PAMPs sensing.
  
  
  
  Excessive death of hepatocytes is a characteristic of liver injury. A new programmed cell death pathway has been described involving upstream death ligands such as TNF and downstream kinases such as RIPK1. Here, we show that in the presence of LPS liver induced hepatic injury was due to secretion of TNF by liver macrophages, and that RIPK1 acts as a powerful protector of hepatocyte death. This newly identified pathway in the liver may be helpful in the management of patients to predict their risk of developing acute liver failure.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France.
authors.forename: Aveline
authors.initials: A
authors.lastname: Filliol
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Piquet-Pellorce
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France; Centre National de la Recherche Scientifique (CNRS), UMR 6290, Institut de Génétique et Développement de Rennes (IGDR), F-35043 Rennes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Raguénès-Nicol
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dion
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Farooq
authors.affiliation: Université de Rennes 1, F-35043 Rennes, France; Service de Biochimie CHU Rennes, Université de Rennes 1; F-35043 Rennes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lucas-Clerc
authors.affiliation: Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: Mathieu J M
authors.initials: MJM
authors.lastname: Bertrand
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Seyec
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Samson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006520:Hepatitis, Animal / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D000069452:Pathogen-Associated Molecular Pattern Molecules / Q000633:toxicity*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D000069452:Pathogen-Associated Molecular Pattern Molecules; D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse
keywords: Acute hepatitis; Cell death; CpG-DNA; Cytokine; DAMPs; Inflammation; LPS; Liver; PAMPs; RIP kinase; RIPK1; TNF-α