Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer

Research output: Contribution to journalArticlepeer-review

Authors

  • Mohsen Malehmir
  • Dominik Pfister
  • Suchira Gallage
  • Marta Szydlowska
  • Donato Inverso
  • Elena Kotsiliti
  • Valentina Leone
  • Moritz Peiseler
  • Bas G J Surewaard
  • Dominik Rath
  • Adnan Ali
  • Monika Julia Wolf
  • Hannah Drescher
  • Marc E Healy
  • Daniel Dauch
  • Daniela Kroy
  • Oliver Krenkel
  • Marlene Kohlhepp
  • Thomas Engleitner
  • Alexander Olkus
  • Tjeerd Sijmonsma
  • Julia Volz
  • Carsten Deppermann
  • David Stegner
  • Patrick Helbling
  • César Nombela-Arrieta
  • Anahita Rafiei
  • Martina Hinterleitner
  • Marcel Rall
  • Florian Baku
  • Oliver Borst
  • Caroline L Wilson
  • Jack Leslie
  • Tracy O'Connor
  • Ana Teijeiro
  • Marco Prinz
  • Ruzhica Bogeska
  • Natasha Anstee
  • Malte N Bongers
  • Mike Notohamiprodjo
  • Tobias Geisler
  • Dominic J Withers
  • Jerry Ware
  • Derek A Mann
  • Hellmut G Augustin
  • Alexandros Vegiopoulos
  • Michael D Milsom
  • Adam J. Rose
  • Josep M Llovet
  • Roser Pinyol
  • Frank Tacke
  • Roland Rad
  • Matthias Matter
  • Nabil Djouder
  • Paul Kubes
  • Percy A Knolle
  • Kristian Unger
  • Lars Zender
  • Bernhard Nieswandt
  • Meinrad Gawaz
  • Achim Weber
  • Mathias Heikenwalder

External organisations

  • University Hospital Zürich
  • Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Heidelberg University
  • Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
  • Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • University of Calgary
  • University Medical Center
  • Eberhard Karls University of Tübingen,
  • Department of Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany.
  • Heidelberg University Hospital
  • University Hospital Würzburg
  • Division of Oncology and Hematology, University Children's Hospital Zurich, Children's Research Center, Zurich, Switzerland.
  • Newcastle University
  • Technical University Munich
  • University of Birmingham
  • Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain.
  • University of Freiburg
  • DKFZ-ZMBH Alliance, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
  • University of Tübingen
  • Imperial College London
  • University of Arkansas
  • DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Institució Catalana de Recerca i Estudis Avançats
  • Universitat de Barcelona
  • University Hospital Basel
  • Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany. heikenwaelder@helmholtz-muenchen.de.
  • DKFZ (German Cancer Research Centre)
  • Monash University

Abstract

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.

Details

Original languageEnglish
Pages (from-to)641-655
Number of pages15
JournalNature Medicine
Volume25
Issue number4
Publication statusPublished - 1 Apr 2019

Keywords

  • Animals, Blood Platelets/drug effects, Body Weight/drug effects, Cytokines/metabolism, Cytoplasmic Granules/drug effects, Endothelium/drug effects, Hepatocytes/drug effects, Humans, Hyaluronan Receptors/metabolism, Hyaluronic Acid/metabolism, Kupffer Cells/drug effects, Liver/drug effects, Liver Neoplasms/blood, Mice, Transgenic, Non-alcoholic Fatty Liver Disease/blood, Platelet Aggregation/drug effects, Platelet Aggregation Inhibitors/pharmacology, Platelet Count, Platelet Glycoprotein GPIb-IX Complex/metabolism

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