Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury
Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury
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DOI：
10.1136/gutjnl-2011-300304
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发表时间：
2012-03-01
期刊：
影响因子：
24.5
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
--
作者：
Baeck, Christer;Wehr, Alexander;Tacke, Frank
目的单核细胞趋化蛋白-1 （MCP-1, CCL2）是趋化因子受体C-C趋化因子受体2 （CCR2）的主要配体，在非酒精性脂肪性肝炎（NASH）患者和脂肪性肝炎和纤维化小鼠模型的肝脏中升高。最近的研究表明，损伤后单核细胞/巨噬细胞浸润到肝脏受到CCL2/CCR2轴的关键调控，对肝脏炎症和纤维化的持续存在具有重要的功能。结构化的l -对映体RNA寡核苷酸mNOX-E36（所谓的Spiegelmer）有效地结合和抑制小鼠MCP-1。在两种慢性肝病小鼠模型中研究了mNOX-E36对MCP-1的药理抑制作用。方法在小鼠急性或慢性四氯化碳（CCl4）和蛋氨酸胆碱缺乏（MCD）饮食引起的慢性肝损伤模型中，观察mNOX-E36对MCP-1的药理抑制作用。结果mNOX-E36拮抗MCP-1能有效抑制小鼠体外单核细胞趋化作用和体内急性中毒性损伤后Gr1(+) （Ly6C(+)）血单核细胞向肝脏的迁移。在CCl4-和MCD饮食诱导的小鼠肝损伤模型中，通过荧光活化细胞分选（FACS）分析和免疫组织化学发现，抗mcp -1处理的小鼠肝脏中巨噬细胞的浸润明显减少。与肝内巨噬细胞水平降低一致，肝组织中的促炎细胞因子（肿瘤坏死因子α、干扰素γ和白细胞介素6）显著降低。抗mcp -1治疗没有显著改变6周（CCl4）或8周（MCD饮食）的总体纤维化进展。然而，在MCD饮食挑战后，在mnox - e36处理的动物中检测到较低水平的脂肪肝变性（组织学评分、油红O染色、肝脏甘油三酯含量、脂肪生成基因）。治疗性给予mNOX-E36也可改善肝脂肪变性。结论通过阻断MCP-1可有效抑制慢性肝损伤过程中肝单核/巨噬细胞的浸润。相关的改善脂肪变性的发展表明，抑制MCP-1是一种有趣的新方法，可用于肝脏炎症和脂肪性肝炎的药物治疗。
Objective Monocyte chemoattractant protein-1 (MCP-1, CCL2), the primary ligand for chemokine receptor C-C chemokine receptor 2 (CCR2), is increased in livers of patients with non-alcoholic steatohepatitis (NASH) and murine models of steatohepatitis and fibrosis. It was recently shown that monocyte/macrophage infiltration into the liver upon injury is critically regulated by the CCL2/CCR2 axis and is functionally important for perpetuating hepatic inflammation and fibrogenesis. The structured L-enantiomeric RNA oligonucleotide mNOX-E36 (a so-called Spiegelmer) potently binds and inhibits murine MCP-1. Pharmacological inhibition of MCP-1 with mNOX-E36 was investigated in two murine models of chronic liver diseases.Methods Pharmacological inhibition of MCP-1 by thrice-weekly mNOX-E36 subcutaneously was tested in murine models of acute or chronic carbon tetrachloride (CCl4)- and methionineecholine-deficient (MCD) diet-induced chronic hepatic injury in vivo.Results Antagonising MCP-1 by mNOX-E36 efficiently inhibited murine monocyte chemotaxis in vitro as well as migration of Gr1(+) (Ly6C(+)) blood monocytes into the liver upon acute toxic injury in vivo. In murine models of CCl4- and MCD diet-induced hepatic injury, the infiltration of macrophages into the liver was significantly decreased in anti-MCP-1-treated mice as found by fluorescence-activated cell sorting (FACS) analysis and immunohistochemistry. In line with lower levels of intrahepatic macrophages, proinflammatory cytokines (tumour necrosis factor alpha, interferon gamma and interleukin 6) were significantly reduced in liver tissue. Overall fibrosis progression over 6 (CCl4) or 8 weeks (MCD diet) was not significantly altered by anti-MCP-1 treatment. However, upon MCD diet challenge a lower level of fatty liver degeneration (histology score, Oil red O staining, hepatic triglyceride content, lipogenesis genes) was detected in mNOX-E36-treated animals. mNOX-E36 also ameliorated hepatic steatosis upon therapeutic administration.Conclusions These results demonstrate the successful pharmacological inhibition of hepatic monocyte/macrophage infiltration by blocking MCP-1 during chronic liver damage in two in vivo models. The associated ameliorated steatosis development suggests that inhibition of MCP-1 is an interesting novel approach for pharmacological treatment in liver inflammation and steatohepatitis.