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

被引：66

作者：

Chauhan, Abhishek ^{[1
,2
]}

Sheriff, Lozan ^{[1
,2
]}

Hussain, Mohammed T. ^{[1
,2
]}

Webb, Gwilym J. ^{[1
,2
]}

Patten, Daniel A. ^{[1
,2
]}

Shepherd, Emma L. ^{[1
,2
]}

Shaw, Robert ^{[3
]}

Weston, Christopher J. ^{[1
,2
]}

Haldar, Debashis ^{[1
,2
]}

Bourke, Samuel ^{[1
,2
]}

Bhandari, Rajan ^{[1
,2
]}

Watson, Stephanie ^{[4
]}

Adams, David H. ^{[1
,2
]}

Watson, Steve P. ^{[4
,5
,6
]}

Lalor, Patricia F. ^{[1
,2
]}

机构：

[1] Univ Birmingham, Sch Med, Ctr Liver & Gastrointestinal Res, Inst Immunol & Inflammat, Birmingham B15 2TT, W Midlands, England

[2] Univ Birmingham, Sch Med, Natl Inst Hlth Res, Birmingham Biomed Res Ctr, Birmingham B15 2TT, W Midlands, England

[3] Univ Birmingham, Coll Med & Dent Sci, Technol Hub, Birmingham B15 2TT, W Midlands, England

[4] Univ Birmingham, Sch Med, Inst Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England

[5] Univ Birmingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham, Midlands, England

[6] Univ Nottingham, Ctr Membrane Prot & Receptors COMPARE, Nottingham, Midlands, England

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

ACTIVATION MOTIF ITAM; STERILE INFLAMMATION; IMMUNE DYSFUNCTION; DEPLETION PROTECTS; SUPPRESSOR-CELLS; INJURY; HEPATOTOXICITY; REGENERATION; MACROPHAGES; MECHANISM;

D O I：

10.1038/s41467-020-15584-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-alpha (TNF-alpha) 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. The molecular mechanisms that drive irreversible acute liver failure remain poorly characterized. Here, the authors show that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage during acute liver injury by blocking restorative neutrophil driven inflammation.

引用

页数：12

共 72 条

[31] Bacterial translocation in acute liver injury induced by D-galactosamine [J].