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
- immune-mediated liver damage
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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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