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

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The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure. / Chauhan, Abhishek; Sheriff, Lozan; Hussain, Mohammed T; Webb, Gwilym J; Patten, Daniel A; Shepherd, Emma L; Shaw, Robert; Weston, Christopher J; Haldar, Debashis; Bourke, Samuel; Bhandari, Rajan; Watson, Stephanie; Adams, David H; Watson, Steve P; Lalor, Patricia F.

In: Nature Communications, Vol. 11, No. 1, 1939, 22.04.2020.

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@article{4f5f5a853c9a440fb1181f9564f9476b,
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.",
author = "Abhishek Chauhan and Lozan Sheriff and Hussain, {Mohammed T} and Webb, {Gwilym J} and Patten, {Daniel A} and Shepherd, {Emma L} and Robert Shaw 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}",
year = "2020",
month = apr,
day = "22",
doi = "10.1038/s41467-020-15584-3",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",
number = "1",

}

RIS

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 L

AU - Shaw, Robert

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

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.

U2 - 10.1038/s41467-020-15584-3

DO - 10.1038/s41467-020-15584-3

M3 - Article

C2 - 32321925

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1939

ER -