Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Department of Health Test and Detection, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Jinan, Shandong, 250014, China.
Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China.
Free Radic Biol Med. 2024 Aug 1;220:154-165. doi: 10.1016/j.freeradbiomed.2024.05.004. Epub 2024 May 6.
Liver fibrosis typically develops as a result of chronic liver injury, which involves inflammatory and regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM2), predominantly expressing in hepatic non-parenchymal cells, plays a crucial role in regulating the function of macrophages. However, its mechanism in liver fibrosis remains poorly defined.
Experimental liver fibrosis models in wild type and TREM2 mice, and in vitro studies with AML-12 cells and Raw264.7 cells were conducted. The expression of TREM2 and related molecular mechanism were evaluated by using samples from patients with liver fibrosis.
We demonstrated that TREM2 was upregulated in murine model with liver fibrosis. Mice lacking TREM2 exhibited reduced phagocytosis activity in macrophages following carbon tetrachloride (CCl) intoxication. As a result, there was an increased accumulation of necrotic apoptotic hepatocytes. Additionally, TREM2 knockout aggravated the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from dead hepatocytes during CCl exposure, and further promoted the occurrence of macrophage-mediated M1 polarization. Then, TREM2 mice showed more serious fibrosis pathological changes. In vitro, the necrotic apoptosis inhibitor GSK872 effectively alleviated the release of mito-DAMPs in AML-12 cells after CCl intoxication, which confirmed that mito-DAMPs originated from dead liver cells. Moreover, direct stimulation of Raw264.7 cells by mito-DAMPs from liver tissue can induce intracellular inflammatory response. More importantly, TREM2 was elevated and inflammatory factors were markedly accumulated surrounding dead cells in the livers of human patients with liver fibrosis.
Our study highlights that TREM2 serves as a negative regulator of liver fibrosis, suggesting its potential as a novel therapeutic target.
肝纤维化通常是由慢性肝损伤引起的，涉及炎症和再生过程。髓样细胞触发受体 2（TREM2）主要在肝非实质细胞中表达，在调节巨噬细胞功能方面发挥着关键作用。然而，其在肝纤维化中的机制仍不清楚。
建立野生型和 Trem2 敲除小鼠实验性肝纤维化模型，以及体外 AML-12 细胞和 Raw264.7 细胞研究，检测肝纤维化患者样本中 TREM2 的表达及相关分子机制。
我们发现肝纤维化小鼠模型中 TREM2 表达上调。四氯化碳（CCl）中毒后，Trem2 缺失小鼠巨噬细胞吞噬活性降低，导致坏死凋亡的肝细胞积聚增加。此外，Trem2 敲除加重了 CCl 暴露时坏死凋亡肝细胞释放线粒体损伤相关分子模式（mito-DAMPs），并进一步促进巨噬细胞介导的 M1 极化。随后，Trem2 敲除小鼠表现出更严重的纤维化病理变化。体外实验中，坏死凋亡抑制剂 GSK872 可有效减轻 CCl 中毒后 AML-12 细胞中 mito-DAMPs 的释放，证实 mito-DAMPs 来源于坏死的肝细胞。此外，肝组织来源的 mito-DAMPs 直接刺激 Raw264.7 细胞可诱导细胞内炎症反应。更重要的是，在肝纤维化患者肝脏中，TREM2 升高且围绕坏死细胞的炎症因子明显积聚。
本研究提示 TREM2 是肝纤维化的负调控因子，为其作为一种新型治疗靶点提供了理论依据。
