Department of Medicine III, University Hospital Aachen, Aachen, Germany.
Hepatology. 2010 Nov;52(5):1769-82. doi: 10.1002/hep.23894.
Chemokines modulate inflammatory responses that are prerequisites for organ fibrosis upon liver injury. Monocyte-derived hepatic macrophages are critical for the development, maintenance, and resolution of hepatic fibrosis. The specific role of monocyte-associated chemokine (C-X3-C motif) receptor 1 (CX₃CR1) and its cognate ligand fractalkine [chemokine (C-X3-C motif) ligand 1)] in liver inflammation and fibrosis is currently unknown. We examined 169 patients with chronic liver diseases and 84 healthy controls; we found that CX₃CL1 is significantly up-regulated in the circulation upon disease progression, whereas CX₃CR1 is down-regulated intrahepatically in patients with advanced liver fibrosis or cirrhosis. To analyze the functional relevance of this pathway, two models of experimental liver fibrosis were applied to wild-type (WT) and CX₃CR1-deficient mice. Fractalkine expression was induced upon liver injury in mice, primarily in hepatocytes and hepatic stellate cells. CX₃CR1(-/-) animals developed greater hepatic fibrosis than WT animals with carbon tetrachloride-induced and bile duct ligation-induced fibrosis. CX₃CR1(-/-) mice displayed significantly increased numbers of monocyte-derived macrophages within the injured liver. Chimeric animals that underwent bone marrow transplantation revealed that CX₃CR1 restricts hepatic fibrosis progression and monocyte accumulation through mechanisms exerted by infiltrating immune cells. In the absence of CX₃CR1, intrahepatic monocytes develop preferentially into proinflammatory tumor necrosis factor-producing and inducible nitric oxide synthase-producing macrophages. CX₃CR1 represents an essential survival signal for hepatic monocyte-derived macrophages by activating antiapoptotic bcl2 expression. Monocytes/macrophages lacking CX₃CR1 undergo increased cell death after liver injury, which then perpetuates inflammation, promotes prolonged inflammatory monocyte infiltration into the liver, and results in enhanced liver fibrosis.
CX₃CR1 limits liver fibrosis in vivo by controlling the differentiation and survival of intrahepatic monocytes. The opposing regulation of CX₃CR1 and fractalkine in patients suggests that pharmacological augmentation of this pathway may represent a possible therapeutic antifibrotic strategy.
趋化因子调节炎症反应，这是肝损伤后器官纤维化的先决条件。单核细胞衍生的肝巨噬细胞对肝纤维化的发展、维持和消退至关重要。单核细胞相关趋化因子（C-X3-C 基序）受体 1（CX₃CR1）及其同源配体 fractalkine[趋化因子（C-X3-C 基序）配体 1]在肝脏炎症和纤维化中的具体作用尚不清楚。我们检查了 169 例慢性肝病患者和 84 例健康对照者；我们发现，随着疾病的进展，CX₃CL1 在循环中显著上调，而 CX₃CR1 在患有晚期肝纤维化或肝硬化的患者中在肝内下调。为了分析该途径的功能相关性，我们将两种实验性肝纤维化模型应用于野生型（WT）和 CX₃CR1 缺陷型小鼠。在小鼠肝损伤时诱导 fractalkine 表达，主要在肝细胞和肝星状细胞中。与四氯化碳诱导和胆管结扎诱导的纤维化相比，CX₃CR1（-/-）动物发展出更大的肝纤维化。CX₃CR1（-/-）小鼠在受损的肝脏中显示出明显更多的单核细胞衍生的巨噬细胞。进行骨髓移植的嵌合动物表明，CX₃CR1 通过浸润免疫细胞发挥作用，限制肝纤维化的进展和单核细胞的积累。在缺乏 CX₃CR1 的情况下，肝内单核细胞优先发展为产生促炎肿瘤坏死因子和诱导型一氧化氮合酶的巨噬细胞。CX₃CR1 通过激活抗凋亡 bcl2 表达，成为肝单核细胞衍生巨噬细胞的必需存活信号。在肝损伤后，缺乏 CX₃CR1 的单核细胞/巨噬细胞发生更多的细胞死亡，进而使炎症持续存在，促进炎症性单核细胞在肝脏中的持续浸润，并导致肝纤维化增强。
CX₃CR1 通过控制肝内单核细胞的分化和存活来限制体内肝纤维化。患者中 CX₃CR1 和 fractalkine 的相反调节表明，该途径的药理学增强可能代表一种潜在的治疗性抗纤维化策略。
