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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.

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



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.


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.


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.


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.


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

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