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 L Shepherd, Robert Shaw, Christopher J Weston, Debashis Haldar, Samuel Bourke, Rajan Bhandari, Stephanie Watson, David H Adams, Steve P Watson, Patricia F Lalor

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8 Citations (Scopus)
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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 languageEnglish
Article number1939
Number of pages12
JournalNature Communications
Volume11
Issue number1
Early online date22 Apr 2020
DOIs
Publication statusPublished - Dec 2020

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