Yang Ying, Ying Gaoxiang, Wu Fengtian, Chen Zhi
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China.
National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China.
Cell Death Discov. 2020 Jul 22;6:62. doi: 10.1038/s41420-020-00299-7. eCollection 2020.
Liver failure (LF) is a monocyte/macrophage-mediated liver injury that has been associated with inflammatory mediators. However, the mechanism through which monocytes/macrophages regulate LF has not been fully elucidated. In this study, we investigated the role of soluble T-cell immunoglobulin domain and mucin domain-containing molecule-3 (sTim-3) in inhibition of release of inflammatory mediators. We further assess this role in protection against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver failure (ALF), via monocyte/macrophage regulation and autophagy induction in mice. Our findings indicate significantly higher plasma sTim-3 in acute-on-chronic liver failure (ACLF) group relative to other groups, with this trend associated with disease progression. Furthermore, infiltrated recombinant sTim-3 inhibited release of various inflammatory mediators, including cytokines and human high-mobility group box-1 (HMGB1), potentially via autophagy induction. Furthermore, H&E staining and the low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ALF mice, supported that recombinant sTim-3 effectively alleviated liver injury. Moreover, sTim-3 induced changes in monocyte/macrophage population in mice's liver or blood, which consequently caused a reduction in proinflammatory CD11bF4/80 monocyte-derived macrophages and Ly-6C(+)CD11b(+) monocytes. Conversely, sTim-3 increased autophagy levels of hepatic CD11b(+) monocyte-derived macrophages and decreased apoptosis rate of CD11b (+) monocytes in the blood. Collectively, our findings demonstrated that sTim-3 alleviated inflammatory response and liver injury by promoting autophagy and regulating monocyte/macrophage function. This indicates its potential for future development of novel therapeutic strategies against LF.
肝衰竭（LF）是一种由单核细胞/巨噬细胞介导的肝损伤，与炎症介质有关。然而，单核细胞/巨噬细胞调节肝衰竭的机制尚未完全阐明。在本研究中，我们研究了可溶性T细胞免疫球蛋白结构域和粘蛋白结构域分子3（sTim-3）在抑制炎症介质释放中的作用。我们通过小鼠单核细胞/巨噬细胞调节和自噬诱导，进一步评估其在预防D-半乳糖胺（D-GalN）/脂多糖（LPS）诱导的急性肝衰竭（ALF）中的作用。我们的研究结果表明，相对于其他组，急性慢性肝衰竭（ACLF）组的血浆sTim-3显著更高，这一趋势与疾病进展相关。此外，浸润的重组sTim-3抑制了包括细胞因子和人高迁移率族蛋白B1（HMGB1）在内的各种炎症介质的释放，可能是通过自噬诱导。此外，ALF小鼠的苏木精-伊红染色以及低水平的丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST），支持重组sTim-3有效减轻肝损伤。此外，sTim-3诱导小鼠肝脏或血液中单核细胞/巨噬细胞群体的变化，从而导致促炎CD11bF4/80单核细胞来源的巨噬细胞和Ly-6C(+)CD11b(+)单核细胞减少。相反，sTim-3增加了肝脏CD11b(+)单核细胞来源的巨噬细胞的自噬水平，并降低了血液中CD11b(+)单核细胞的凋亡率。总体而言，我们的研究结果表明，sTim-3通过促进自噬和调节单核细胞/巨噬细胞功能减轻炎症反应和肝损伤。这表明其在未来开发针对肝衰竭的新型治疗策略方面具有潜力。
