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Gut. 2018 Jan 27. pii: gutjnl-2017-314107. doi: 10.1136/gutjnl-2017-314107. [Epub ahead of print]

Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage.

Author information

1
Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
2
Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), San Sebastian, Spain.
3
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
4
CIBERehd, Instituto de Salud Carlos III, San Sebastián, Spain.
5
CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
6
Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
7
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
8
Hepatology Programme, CIMA, University of Navarra, Pamplona, Spain.
9
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
10
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
#
Contributed equally

Abstract

OBJECTIVE:

Liver injury impacts hepatic inflammation in part via Toll-like receptor (TLR) signalling. Triggering receptor expressed on myeloid cells 2 (TREM-2) modulates TLR4-mediated inflammation in bone marrow (BM)-derived macrophages but its function in liver injury is unknown. Here we hypothesised that the anti-inflammatory effects of TREM-2 on TLR signalling may limit hepatic injury.

DESIGN:

TREM-2 expression was analysed in livers of humans with various forms of liver injury compared with control individuals. Acute and chronic liver injury models were performed in wild type and Trem-2-/- mice. Primary liver cells from both genotypes of mice were isolated for in vitro experiments.

RESULTS:

TREM-2 was expressed on non-parenchymal hepatic cells and induced during liver injury in mice and man. Mice lacking TREM-2 exhibited heightened liver damage and inflammation during acute and repetitive carbon tetrachloride and acetaminophen (APAP) intoxication, the latter of which TREM-2 deficiency was remarkably associated with worsened survival. Liver damage in Trem-2-/- mice following chronic injury and APAP challenge was associated with elevated hepatic lipid peroxidation and macrophage content. BM transplantation experiments and cellular reactive oxygen species assays revealed effects of TREM-2 in the context of chronic injury depended on both immune and resident TREM-2 expression. Consistent with effects of TREM-2 on inflammation-associated injury, primary hepatic macrophages and hepatic stellate cells lacking TREM-2 exhibited augmented TLR4-driven proinflammatory responses.

CONCLUSION:

Our data indicate that by acting as a natural brake on inflammation during hepatocellular injury, TREM-2 is a critical regulator of diverse types of hepatotoxic injury.

KEYWORDS:

acute liver failure; chronic liver disease; hepatic stellate cell; immune-mediated liver damage; inflammation

PMID:
29374630
DOI:
10.1136/gutjnl-2017-314107
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