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)
183 Downloads (Pure)

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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