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

• Published in: Gut Vol. 68; no. 3; pp. 533 - 546
• Main Authors: Perugorria, Maria J, Esparza-Baquer, Aitor, Oakley, Fiona, Labiano, Ibone, Korosec, Ana, Jais, Alexander, Mann, Jelena, Tiniakos, Dina, Santos-Laso, Alvaro, Arbelaiz, Ander, Gawish, Riem, Sampedro, Ana, Fontanellas, Antonio, Hijona, Elizabeth, Jimenez-Agüero, Raul, Esterbauer, Harald, Stoiber, Dagmar, Bujanda, Luis, Banales, Jesus María, Knapp, Sylvia, Sharif, Omar, Mann, Derek A
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.03.2019; BMJ Publishing Group
• Series: Original article
• Subjects: Acetaminophen; Aged; Alcohol; Analgesics; Animal models; Animals; Bone marrow; Carbon; Carbon Tetrachloride; Case-Control Studies; Chemokines; Cytokines; Ethics; Female; Gene expression; Genotypes; Hematopoietic Stem Cells - metabolism; Hepatocytes; Hepatocytes - metabolism; Hepatology; Humans; Inflammation; Inflammation Mediators - metabolism; Intoxication; Kinases; Kupffer Cells - metabolism; Lipid peroxidation; Lipid Peroxidation - physiology; Liver - metabolism; Liver Cirrhosis - etiology; Liver Cirrhosis - immunology; Liver Cirrhosis - metabolism; Liver Cirrhosis, Experimental - immunology; Liver Cirrhosis, Experimental - metabolism; Liver diseases; Macrophages; Male; Medical research; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Mice, Knockout; Middle Aged; Myeloid cells; Pathogenesis; Patients; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Immunologic - deficiency; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Receptors, Immunologic - physiology; Rodents; Stellate cells; TLR4 protein; Toll-Like Receptor 4 - physiology; Toll-like receptors; Transplantation; Up-Regulation - physiology; United Kingdom > UK; chronic liver disease; hepatic stellate cell; acute liver failure; inflammation; immune-mediated liver damage
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2017-314107

ObjectiveLiver 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.DesignTREM-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.ResultsTREM-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.ConclusionOur 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.