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 CD11b^hiF4/80^lo 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）是单核细胞/巨噬细胞介导的肝损伤，与炎症介质相关。然而，单核细胞/巨噬细胞调节 LF 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含有粘蛋白结构域的分子 3 (sTim-3) 在抑制炎症介质释放中的作用。我们进一步评估了通过单核细胞/巨噬细胞调节和自噬诱导在小鼠中预防 D-半乳糖胺 (D-GalN)/脂多糖 (LPS) 诱导的急性肝衰竭 (ALF) 的作用。我们的研究结果表明，慢性肝衰竭急性发作 (ACLF) 组的血浆 sTim-3 显着高于其他组，这种趋势与疾病进展相关。此外，浸润的重组 sTim-3 可能通过自噬诱导抑制多种炎症介质的释放，包括细胞因子和人高迁移率族蛋白 1 (HMGB1)。此外，H&E 染色以及 ALF 小鼠的丙氨酸转氨酶 (ALT) 和天冬氨酸转氨酶 (AST) 水平较低，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/巨噬细胞群的变化，从而导致促炎性CD11b ^hi F4/80 ^lo单核细胞衍生的巨噬细胞和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。总的来说，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。这表明其未来开发针对 LF 的新型治疗策略的潜力。