CX3CR1⁺ cells play a crucial role in liver fibrosis progression. However, changes in the migratory behavior and spatial distribution of spleen-derived and hepatic CX3CR1⁺ cells in the fibrotic liver as well as their influence on the liver fibrosis remain unclear./nMethods: The CX3CR1^GFP/+ transgenic mice and CX3CR1-KikGR transgenic mice were used to establish the CCl4-induced liver fibrosis model. Splenectomy, adoptive transfusion of splenocytes, in vivo photoconversion of splenic CX3CR1⁺ cells and intravital imaging were performed to study the spatial distribution, migration and movement behavior, and regulatory function of CX3CR1⁺ cells in liver fibrosis./nResults: Intravital imaging revealed that the CX3CR1^GFP cells accumulated into the fibrotic liver and tended to accumulate towards the central vein (CV) in the hepatic lobules. Two subtypes of hepatic CX3CR1⁺ cells existed in the fibrotic liver. The first subtype was the interacting CX3CR1^GFP cells, most of which were observed to distribute in the liver parenchyma and had a higher process velocity; the second subtype was mobile CX3CR1^GFP cells, most of which were present in the hepatic vessels with a faster moving speed. Splenectomy ameliorated liver fibrosis and decreased the number of CX3CR1⁺ cells in the fibrotic liver. Moreover, splenectomy rearranged CX3CR1^GFP cells to the boundary of the hepatic lobule, reduced the process velocity of interacting CX3CR1^GFP cells and decreased the number and mobility of mobile CX3CR1^GFP cells in the fibrotic liver. Transfusion of spleen-derived classical monocytes increased the process velocity and mobility of hepatic endogenous CX3CR1^GFP cells and facilitated liver fibrosis progression via the production of proinflammatory and profibrotic cytokines. The photoconverted splenic CX3CR1⁺ KikRed⁺ cells were observed to leave the spleen, accumulate into the fibrotic liver and contact with hepatic CX3CR1⁺ KikGreen⁺ cells during hepatic fibrosis./nConclusion: The splenic CX3CR1⁺ monocytes with classical phenotype migrated from the spleen to the fibrotic liver, modifying the migratory behavior of hepatic endogenous CX3CR1^GFP cells and exacerbating liver fibrosis via the secretion of cytokines. This study reveals that splenic CX3CR1⁺ classical monocytes are a key driver of liver fibrosis via the spleen-liver axis and may be potential candidate targets for the treatment of chronic liver fibrosis.

中文翻译：

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脾脏经典单核细胞改变肝脏 CX3CR1+ 细胞运动通过脾肝轴加剧肝纤维化的活体成像

CX3CR1 ⁺细胞在肝纤维化进展中发挥着至关重要的作用。然而，脾源性和肝源性CX3CR1 ⁺细胞在纤维化肝脏中的迁移行为和空间分布的变化以及它们对肝纤维化的影响仍不清楚。/n方法：CX3CR1 ^GFP/+转基因小鼠和CX3CR1-KikGR转基因小鼠采用小鼠建立CCl4诱导的肝纤维化模型。通过脾切除、脾细胞过继性输注、脾CX3CR1 ^+细胞体内光转换和活体成像，研究CX3CR1 ⁺细胞的空间分布、迁移和运动行为以及肝纤维化中的调节功能。/n结果：活体成像显示， CX3CR1 ^GFP细胞积聚到纤维化肝脏中，并倾向于向肝小叶中的中央静脉 (CV) 积聚。纤维化肝脏中存在两种亚型的肝CX3CR1 ⁺细胞。第一个亚型是相互作用的CX3CR1 ^GFP细胞，大多数细胞分布在肝实质中，并且具有较高的处理速度；第二种亚型是移动的CX3CR1 ^GFP细胞，大部分存在于肝血管中，移动速度较快。脾切除术改善了肝纤维化并减少了纤维化肝脏中CX3CR1 ⁺细胞的数量。此外，脾切除将CX3CR1 ^GFP细胞重新排列到肝小叶边界，降低了相互作用的CX3CR1 ^GFP细胞的处理速度，并减少了纤维化肝脏中移动CX3CR1 ^GFP细胞的数量和活动性。脾源性经典单核细胞的输注增加了肝内源性 CX3CR1 ^GFP细胞的处理速度和活动性，并通过产生促炎和促纤维化细胞因子促进肝纤维化进展。观察到光转化的脾CX3CR1 ⁺ KikRed ⁺细胞离开脾脏，积累到纤维化肝脏中，并在肝纤维化过程中与肝脏CX3CR1 ⁺ KikGreen ⁺细胞接触。/n结论：具有经典表型的脾CX3CR1 ⁺单核细胞从脾迁移到肝脏纤维化肝脏，改变肝内源性 CX3CR1 ^GFP细胞的迁移行为，并通过细胞因子的分泌加剧肝纤维化。这项研究表明脾脏 CX3CR1 ⁺经典单核细胞是通过脾肝轴引起肝纤维化的关键驱动因素，可能是治疗慢性肝纤维化的潜在候选靶点。