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Original Article
Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage
  1. Maria J Perugorria1,2,3,4,
  2. Aitor Esparza-Baquer2,
  3. Fiona Oakley1,
  4. Ibone Labiano2,
  5. Ana Korosec5,6,
  6. Alexander Jais7,
  7. Jelena Mann1,
  8. Dina Tiniakos1,
  9. Alvaro Santos-Laso2,
  10. Ander Arbelaiz2,
  11. Riem Gawish5,6,
  12. Ana Sampedro8,
  13. Antonio Fontanellas8,
  14. Elizabeth Hijona2,4,
  15. Raul Jimenez-Agüero2,
  16. Harald Esterbauer7,
  17. Dagmar Stoiber9,10,
  18. Luis Bujanda2,4,
  19. Jesus María Banales2,3,4,
  20. Sylvia Knapp5,6,
  21. Omar Sharif5,6,10,
  22. Derek A Mann1
  1. 1Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  2. 2Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), San Sebastian, Spain
  3. 3IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  4. 4CIBERehd, Instituto de Salud Carlos III, San Sebastián, Spain
  5. 5CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  6. 6Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria
  7. 7Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
  8. 8Hepatology Programme, CIMA, University of Navarra, Pamplona, Spain
  9. 9Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
  10. 10Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
  1. Correspondence to Dr Maria J Perugorria, Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), CIBERehd, 20014 San Sebastian, Spain; matxus.perugorria{at}biodonostia.org, Dr Omar Sharif, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, and Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria ; Omar.Sharif{at}lbicr.lbg.ac.at and Prof Derek A Mann, Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, 4th Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; derek.mann{at}newcastle.ac.uk

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.

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

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Footnotes

  • OS and DAM contributed equally.

  • Contributors MJP, FO, AE-B, IL, AK, AJ, JM, DT, AS-L, AA, RG, AS, AF, HE, RJ-A, HE, DS, LB, JMB and OS performed experiments. MJP, SK, OS and DAM discussed and interpreted the data. MJP, OS and DAM wrote the manuscript. OS and DAM share senior authorship.

  • Funding The present study was supported by grants from the Wellcome Trust (grant WT086755MA), European Commission FP7 program grant ’INFLA-CARE' (EC Contract No. 223151;), the Medical Research Council, UK (grant MR/K001949/1) and Cancer Research UK Programme Grant C18342/A2390. to DAM. The study was also funded by the Basque Government’s Department of Industry, Innovation, Commerce and Tourism, SAIOTEK Programme grant (SAIO13-PE13BN010) and the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III grant (PI14/00399), both to MJP. MJP was funded by IKERBASQUE, Basque foundation for Science and the Ministry of Economy and Competitiveness, Ramón y Cajal Programme (RYC-2015-17755). AE-B was funded by the University of the Basque Country (UPV/EHU; PIF2014/11). IL was funded by the Department of Education, Language Policy and Culture of the Basque Government (PRE_2016_1_0152). RG was funded by the Austrian Science Fund (FWF; APW01205FW, within the Doctoral Program Cell Communication in Health and Disease, CCHD; to SK). OS and SK were funded by the Austrian Science Fund (OS, FWF-25801; SK, Grant I 289-B09).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Clinical Research Ethics Committees of the Basque Country and Donostia Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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