Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), San Sebastian, Spain.
Gut. 2019 Mar;68(3):533-546. doi: 10.1136/gutjnl-2017-314107. Epub 2018 Jan 27.
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.
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 mice. Primary liver cells from both genotypes of mice were isolated for in vitro experiments.
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 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.
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.
肝损伤通过 Toll 样受体（TLR）信号在一定程度上影响肝炎症。髓样细胞表达的触发受体 2（TREM-2）调节骨髓（BM）来源的巨噬细胞中 TLR4 介导的炎症，但它在肝损伤中的功能尚不清楚。在这里，我们假设 TREM-2 对 TLR 信号的抗炎作用可能限制肝损伤。
分析了各种类型肝损伤患者与对照个体相比肝组织中 TREM-2 的表达。在野生型和 小鼠中进行了急性和慢性肝损伤模型。从小鼠的两种基因型中分离出原代肝细胞进行体外实验。
TREM-2 在非实质细胞上表达，并在小鼠和人类的肝损伤中诱导。缺乏 TREM-2 的小鼠在急性和重复四氯化碳和对乙酰氨基酚（APAP）中毒期间表现出更高的肝损伤和炎症，后者与 TREM-2 缺乏导致的存活率显著降低有关。慢性损伤和 APAP 挑战后 小鼠的肝损伤与肝脂质过氧化和巨噬细胞含量升高有关。BM 移植实验和细胞活性氧物质测定表明，慢性损伤背景下 TREM-2 的作用取决于免疫和固有 TREM-2 的表达。与 TREM-2 对炎症相关损伤的作用一致，缺乏 TREM-2 的原代肝巨噬细胞和肝星状细胞表现出增强的 TLR4 驱动的促炎反应。
我们的数据表明，TREM-2 通过在肝细胞损伤过程中充当炎症的天然制动器，是多种类型肝毒性损伤的关键调节剂。
