Korosec, A. (Ana)

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    Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage
    (BMJ, 2019) Banales, J.M. (Jesús M.); Stoiber, D. (Dagmar); Arbelaiz, A. (Ander); Oakley, F. (Fiona); Esterbauer, H. (Harald); Sharif, O. (Omar); Jimenez-Agüero, R. (Raul); Perugorria, M.J. (María J.); Mann, D.A. (Derek A.); Mann, J. (Jelena); Tiniakos, D. (Dina); Korosec, A. (Ana); Bujanda, L. (Luis); Hijona, E. (Elizabeth); Knapp, S. (Sylvia); Fontanellas-Romá, A. (Antonio); Labiano, I. (Ibone); Sampedro, A. (Ana); Santos-Laso, A. (Alvaro); Gawish, R. (Riem); Jais, A. (Alexander); Esparza-Baquer, A. (Aitor)
    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.