title: Opposing role of tumor necrosis factor receptor 1 signaling in T cell-mediated hepatitis and bacterial infection in mice.
abstract: Death receptor (DR) ligands such as tumor necrosis factor (TNF) have been identified as fundamental mediators of liver damage both in mouse models and in humans. While the essential site of function of DR signaling is conceivably the hepatocyte, a systematic analysis is missing. Using mice with conditional gene ablation, we analyzed the tissue-specific function of DR signaling in T cell-dependent (concanavalin A) and independent (lipopolysaccharide/galactosamine) hepatitis and in models of bacterial infection (Listeria monocytogenes, lipopolysaccharide). We report that lipopolysaccharide/galactosamine-induced liver injury depends on hepatocyte-intrinsic TNF receptor 1 (p55, TNFR1). In contrast, we show that T cell-induced hepatitis was independent of TNFR1 signaling in hepatocytes, T cells, or endothelial cells. Moreover, T cell-induced hepatitis was independent of hepatocyte-intrinsic Fas-associated protein with death domain, TNF-related apoptosis-inducing ligand receptor, or Fas signaling. Instead, concanavalin A-induced hepatitis was completely prevented in mice with myeloid-derived cell (MDC)-specific deletion of TNFR1. Significantly, however, mice lacking TNFR1 in MDCs succumbed to listeria infection, although they displayed similar sensitivity toward endotoxin-induced septic shock when compared to control mice. These results suggest that TNFR1 signaling in MDCs is a critical mediator of both the detrimental and the protective functions of TNF in T cell-induced hepatitis and bacterial infection, respectively.
  
  
  
  The critical site of action of DRs is completely dependent on the nature of hepatitis; the data specify MDCs as the essential cell type of TNFR1 function in T cell-mediated hepatitis and in the response to listeria, thereby identifying the opposing role of MDC TNFR1 in autoimmunity and bacterial infection. (Hepatology 2016;64:508-521).
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Collaborative Research Centre 841, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Raluca
authors.initials: R
authors.lastname: Wroblewski
authors.affiliation: Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Marietta
authors.initials: M
authors.lastname: Armaka
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.|Centre for Molecular Medicine, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Vangelis
authors.initials: V
authors.lastname: Kondylis
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.|Centre for Molecular Medicine, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.affiliation: Collaborative Research Centre 841, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Mittrücker
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Collaborative Research Centre 841, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Collaborative Research Centre 841, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.|Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.affiliation: I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Collaborative Research Centre 841, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Ehlken
mesh_terms: D000818:Animals; D003208:Concanavalin A; D042783:Endothelial Cells / Q000378:metabolism; D006520:Hepatitis, Animal / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008070:Lipopolysaccharides; D008089:Listeria monocytogenes; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D003208:Concanavalin A