Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
Technology Hub, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
Nat Commun. 2020 Apr 22;11(1):1939. doi: 10.1038/s41467-020-15584-3.
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.
对乙酰氨基酚（APAP）是西方急性肝衰竭的主要原因。急性肝衰竭（ALF）的特效治疗方法有限且依赖于时间。导致不可逆性急性肝衰竭的机制仍未得到很好的描述。在这里，我们报告说，最近发现的血小板受体 CLEC-2（C 型凝集素样受体）在毒性肝损伤后会持续加重肝损伤。我们的数据表明，阻断血小板 CLEC-2 信号可以通过增加肿瘤坏死因子-α（TNF-α）的产生来增强急性毒性肝损伤（APAP 和四氯化碳）后的肝恢复，然后增强修复性肝中性粒细胞的募集。我们提供了来自人和小鼠的数据，表明血小板 CLEC-2 影响肝脏无菌性炎症反应，并且可以对急性肝损伤进行治疗干预。由于 CLEC-2 介导的血小板激活独立于主要止血途径，因此阻断该途径代表了急性肝衰竭中一种不影响凝血功能、特异性和新颖的治疗方法。
