The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

Abhishek Chauhan; Lozan Sheriff; Mohammed T Hussain; Gwilym J Webb; Daniel A Patten; Emma Louise Shepherd; Robert K Shaw; Christopher J Weston; Debashis Haldar; Samuel Bourke; Rajan Bhandari; Stephanie Watson; David H. Adams; Steve P. Watson; Patricia F. Lalor

doi:10.1038/s41467-020-15584-3

The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

Abhishek Chauhan^*, Lozan Sheriff, Mohammed T Hussain, Gwilym J Webb, Daniel A Patten, Emma Louise Shepherd, Robert K Shaw, Christopher J Weston, Debashis Haldar, Samuel Bourke, Rajan Bhandari, Stephanie Watson, David H. Adams, Steve P. Watson, Patricia F. Lalor

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.

Original language	English
Article number	1939
Number of pages	12
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15584-3
Publication status	Published - 22 Apr 2020

Bibliographical note

Keywords

Acetaminophen/adverse effects
Animals
Blood Platelets/immunology
Carbon Tetrachloride/adverse effects
Chemical and Drug Induced Liver Injury/etiology
Humans
Lectins, C-Type/genetics
Liver/drug effects
Mice
Mice, Inbred C57BL
Neutrophils/immunology
Tumor Necrosis Factor-alpha/genetics

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The_platelet_receptor_CLEC-2_blocks_neutrophil_mediated_hepatic_recovery_in_acetaminophen_induced_acute_liver_failure
© The Author(s) 2020 This article is licensed under a Creative Commons Attribution 4.0 International License, to view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
Final published version, 5.08 MBLicence: CC BY 4.0

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Chauhan, A., Sheriff, L., Hussain, M. T., Webb, G. J., Patten, D. A., Shepherd, E. L., Shaw, R. K., Weston, C. J., Haldar, D., Bourke, S., Bhandari, R., Watson, S., Adams, D. H., Watson, S. P., & Lalor, P. F. (2020). The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure. Nature Communications, 11(1), Article 1939. https://doi.org/10.1038/s41467-020-15584-3

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title = "The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure",

abstract = "Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.",

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author = "Abhishek Chauhan and Lozan Sheriff and Hussain, {Mohammed T} and Webb, {Gwilym J} and Patten, {Daniel A} and Shepherd, {Emma Louise} and Shaw, {Robert K} and Weston, {Christopher J} and Debashis Haldar and Samuel Bourke and Rajan Bhandari and Stephanie Watson and Adams, {David H.} and Watson, {Steve P.} and Lalor, {Patricia F.}",

note = "{\textcopyright} The Author(s) 2020 This article is licensed under a Creative Commons Attribution 4.0 International License, to view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. ",

year = "2020",

month = apr,

day = "22",

doi = "10.1038/s41467-020-15584-3",

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Chauhan, A, Sheriff, L, Hussain, MT, Webb, GJ, Patten, DA, Shepherd, EL, Shaw, RK, Weston, CJ, Haldar, D, Bourke, S, Bhandari, R, Watson, S, Adams, DH, Watson, SP & Lalor, PF 2020, 'The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure', Nature Communications, vol. 11, no. 1, 1939. https://doi.org/10.1038/s41467-020-15584-3

TY - JOUR

T1 - The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

AU - Chauhan, Abhishek

AU - Sheriff, Lozan

AU - Hussain, Mohammed T

AU - Webb, Gwilym J

AU - Patten, Daniel A

AU - Shepherd, Emma Louise

AU - Shaw, Robert K

AU - Weston, Christopher J

AU - Haldar, Debashis

AU - Bourke, Samuel

AU - Bhandari, Rajan

AU - Watson, Stephanie

AU - Adams, David H.

AU - Watson, Steve P.

AU - Lalor, Patricia F.

N1 - © The Author(s) 2020 This article is licensed under a Creative Commons Attribution 4.0 International License, to view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

PY - 2020/4/22

Y1 - 2020/4/22

N2 - Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.

AB - Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.

KW - Acetaminophen/adverse effects

KW - Animals

KW - Blood Platelets/immunology

KW - Carbon Tetrachloride/adverse effects

KW - Chemical and Drug Induced Liver Injury/etiology

KW - Humans

KW - Lectins, C-Type/genetics

KW - Liver/drug effects

KW - Mice

KW - Mice, Inbred C57BL

KW - Neutrophils/immunology

KW - Tumor Necrosis Factor-alpha/genetics

UR - https://www.nature.com/articles/s41467-020-15584-3#additional-information

U2 - 10.1038/s41467-020-15584-3

DO - 10.1038/s41467-020-15584-3

M3 - Article

C2 - 32321925

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1939

ER -

The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

Abstract

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Keywords

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