Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for Charcot-Marie-Tooth 1X
Attenuation of MCP-1/CCL2 expression ameliorates neuropathy in a mouse model for Charcot-Marie-Tooth 1X
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DOI：
10.1093/hmg/ddq269
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发表时间：
2010-09-15
影响因子：
3.5
通讯作者：
Martini, Rudolf
中科院分区：
文献类型：
--
作者：
Groh, Janos;Heinl, Kristina;Martini, Rudolf
趋化因子单核细胞趋化蛋白-1（MCP-1/CCL 2）先前已被证明是两种不同遗传性神经病（Charcot-Marie-Tooth（CMT）1A和1B）模型中巨噬细胞相关神经损伤的重要介质。在差距连接蛋白连接蛋白32（Cx 32 def）缺陷的小鼠中，我们通过将Cx 32 def小鼠与MCP-1敲除突变体杂交，研究了趋化因子在巨噬细胞迁移和神经损伤中的作用。在典型地表达增加水平的MCP-1的Cx 32 def突变体中，巨噬细胞数量强烈升高，这是由MCP-1介导的造血巨噬细胞的流入引起的。奇怪的是，MCP-1的完全基因缺失并没有由于驻留巨噬细胞的代偿性增殖而导致神经中巨噬细胞数量的减少。相反，正如在其他CMT模型中已经看到的，MCP-1的杂合缺失导致吞噬巨噬细胞数量减少和脱髓鞘减轻。而减轻脱髓鞘是短暂的，轴突损伤持续改善，甚至强大的轴突发芽是在12个月检测。其他轴突相关的功能是减轻电生理参数，减少肌肉去神经支配和萎缩，并增加肌肉力量。与CMT 1A和CMT 1B的模型相似，我们鉴定了MEK-ERK信号传导介导Cx 32缺陷型雪旺细胞中MCP-1的表达。通过抑制剂CI-1040阻断这一途径导致MCP-1表达减少，巨噬细胞增加减弱，髓鞘和轴突相关改变改善。因此，通过抑制ERK磷酸化减弱MCP-1上调可能是治疗CMT 1X和其他迄今无法治疗的人类遗传性周围神经病的有希望的方法。
The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been previously shown to be an important mediator of macrophage-related neural damage in models of two distinct inherited neuropathies, Charcot-Marie-Tooth (CMT) 1A and 1B. In mice deficient in the gap junction protein connexin 32 (Cx32def), an established model for the X-chromosome-linked dominant form of CMT (CMT1X), we investigated the role of the chemokine in macrophage immigration and neural damage by crossbreeding the Cx32def mice with MCP-1 knockout mutants. In Cx32def mutants typically expressing increased levels of MCP-1, macrophage numbers were strongly elevated, caused by an MCP-1-mediated influx of haematogenous macrophages. Curiously, the complete genetic deletion of MCP-1 did not cause reduced macrophage numbers in the nerves due to compensatory proliferation of resident macrophages. In contrast, and as already seen in other CMT models, heterozygous deletion of MCP-1 led to reduced numbers of phagocytosing macrophages and an alleviation of demyelination. Whereas alleviated demyelination was transient, axonal damage was persistently improved and even robust axonal sprouting was detectable at 12 months. Other axon-related features were alleviated electrophysiological parameters, reduced muscle denervation and atrophy, and increased muscle strength. Similar to models for CMT1A and CMT1B, we identified MEK-ERK signalling as mediating MCP-1 expression in Cx32-deficient Schwann cells. Blocking this pathway by the inhibitor CI-1040 caused reduced MCP-1 expression, attenuation of macrophage increase and amelioration of myelin- and axon-related alterations. Thus, attenuation of MCP-1 upregulation by inhibiting ERK phosphorylation might be a promising approach to treat CMT1X and other so far untreatable inherited peripheral neuropathies in humans.