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

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; Christopher J Weston; David H Adams; Lozan Sheriff; 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; Patricia F. Lalor; 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

doi:10.1038/s41591-019-0379-5

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

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 OlkusTjeerd 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, Christopher J Weston, David H Adams, Lozan Sheriff, 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, Patricia F. Lalor, 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

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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.

Original language	English
Pages (from-to)	641-655
Number of pages	15
Journal	Nature Medicine
Volume	25
Issue number	4
DOIs	https://doi.org/10.1038/s41591-019-0379-5
Publication status	Published - 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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Malehmir, M., Pfister, D., Gallage, S., Szydlowska, M., Inverso, D., Kotsiliti, E., Leone, V., Peiseler, M., Surewaard, B. G. J., Rath, D., Ali, A., Wolf, M. J., Drescher, H., Healy, M. E., Dauch, D., Kroy, D., Krenkel, O., Kohlhepp, M., Engleitner, T., ... Heikenwalder, M. (2019). Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature Medicine, 25(4), 641-655. https://doi.org/10.1038/s41591-019-0379-5

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title = "Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer",

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.",

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",

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

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day = "1",

doi = "10.1038/s41591-019-0379-5",

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Malehmir, M, Pfister, D, Gallage, S, Szydlowska, M, Inverso, D, Kotsiliti, E, Leone, V, Peiseler, M, Surewaard, BGJ, Rath, D, Ali, A, Wolf, MJ, Drescher, H, Healy, ME, Dauch, D, Kroy, D, Krenkel, O, Kohlhepp, M, Engleitner, T, Olkus, A, Sijmonsma, T, Volz, J, Deppermann, C, Stegner, D, Helbling, P, Nombela-Arrieta, C, Rafiei, A, Hinterleitner, M, Rall, M, Baku, F, Borst, O, Wilson, CL, Leslie, J, O'Connor, T, Weston, CJ , Adams, DH , Sheriff, L, Teijeiro, A, Prinz, M, Bogeska, R, Anstee, N, Bongers, MN, Notohamiprodjo, M, Geisler, T, Withers, DJ, Ware, J, Mann, DA, Augustin, HG, Vegiopoulos, A, Milsom, MD, Rose, AJ, Lalor, PF, Llovet, JM, Pinyol, R, Tacke, F, Rad, R, Matter, M, Djouder, N, Kubes, P, Knolle, PA, Unger, K, Zender, L, Nieswandt, B, Gawaz, M, Weber, A & Heikenwalder, M 2019, 'Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer', Nature Medicine, vol. 25, no. 4, pp. 641-655. https://doi.org/10.1038/s41591-019-0379-5

TY - JOUR

T1 - Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer

AU - Malehmir, Mohsen

AU - Pfister, Dominik

AU - Gallage, Suchira

AU - Szydlowska, Marta

AU - Inverso, Donato

AU - Kotsiliti, Elena

AU - Leone, Valentina

AU - Peiseler, Moritz

AU - Surewaard, Bas G J

AU - Rath, Dominik

AU - Ali, Adnan

AU - Wolf, Monika Julia

AU - Drescher, Hannah

AU - Healy, Marc E

AU - Dauch, Daniel

AU - Kroy, Daniela

AU - Krenkel, Oliver

AU - Kohlhepp, Marlene

AU - Engleitner, Thomas

AU - Olkus, Alexander

AU - Sijmonsma, Tjeerd

AU - Volz, Julia

AU - Deppermann, Carsten

AU - Stegner, David

AU - Helbling, Patrick

AU - Nombela-Arrieta, César

AU - Rafiei, Anahita

AU - Hinterleitner, Martina

AU - Rall, Marcel

AU - Baku, Florian

AU - Borst, Oliver

AU - Wilson, Caroline L

AU - Leslie, Jack

AU - O'Connor, Tracy

AU - Weston, Christopher J

AU - Adams, David H

AU - Sheriff, Lozan

AU - Teijeiro, Ana

AU - Prinz, Marco

AU - Bogeska, Ruzhica

AU - Anstee, Natasha

AU - Bongers, Malte N

AU - Notohamiprodjo, Mike

AU - Geisler, Tobias

AU - Withers, Dominic J

AU - Ware, Jerry

AU - Mann, Derek A

AU - Augustin, Hellmut G

AU - Vegiopoulos, Alexandros

AU - Milsom, Michael D

AU - Rose, Adam J.

AU - Lalor, Patricia F.

AU - Llovet, Josep M

AU - Pinyol, Roser

AU - Tacke, Frank

AU - Rad, Roland

AU - Matter, Matthias

AU - Djouder, Nabil

AU - Kubes, Paul

AU - Knolle, Percy A

AU - Unger, Kristian

AU - Zender, Lars

AU - Nieswandt, Bernhard

AU - Gawaz, Meinrad

AU - Weber, Achim

AU - Heikenwalder, Mathias

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Platelets/drug effects

KW - Body Weight/drug effects

KW - Cytokines/metabolism

KW - Cytoplasmic Granules/drug effects

KW - Endothelium/drug effects

KW - Hepatocytes/drug effects

KW - Humans

KW - Hyaluronan Receptors/metabolism

KW - Hyaluronic Acid/metabolism

KW - Kupffer Cells/drug effects

KW - Liver/drug effects

KW - Liver Neoplasms/blood

KW - Mice, Transgenic

KW - Non-alcoholic Fatty Liver Disease/blood

KW - Platelet Aggregation/drug effects

KW - Platelet Aggregation Inhibitors/pharmacology

KW - Platelet Count

KW - Platelet Glycoprotein GPIb-IX Complex/metabolism

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UR - https://publons.com/publon/19039807/

U2 - 10.1038/s41591-019-0379-5

DO - 10.1038/s41591-019-0379-5

M3 - Article

C2 - 30936549

SN - 1078-8956

VL - 25

SP - 641

EP - 655

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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