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