Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage.
Gut
; 68(3): 533-546, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-29374630
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
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Receptores Imunológicos
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Fígado
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Cirrose Hepática
Tipo de estudo:
Etiology_studies
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Observational_studies
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Risk_factors_studies
Limite:
Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Gut
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido