It remains controversial whether circulating monocytes expressing CCR2 infiltrate the central nervous system (CNS) and contribute to pathogenicity of amyotrophic lateral sclerosis (ALS). A previous report used conventional immunohistochemistry to show that CCR2 is exclusively expressed by astrocytes, but not infiltrating monocytes/microglia or neurons, in the spinal cords of ALS model mice. In this study, we assessed the cellular distribution of CCR2 in the CNS of ALS mice using CCR2-reporter mice (Ccr2rfp/+-Cx3cr1gfp/+-SOD1G93A Tg mice), a more sophisticated method for directly detecting the distribution of CCR2 protein. We found that infiltration of CCR2+ monocytes in the lumbar spinal cord increased over the course of disease progression. Moreover, from the middle stage of disease, CCR2 was partially distributed in microglia and neurons, but not astrocytes, in striking contrast to the previous findings. These novel observations suggested that CCR2+ monocyte infiltration leads to CNS environmental deterioration due to toxic conversion of microglia and neurons, creating a vicious cycle of neuroinflammation and leading to acceleration of ALS pathology. Our findings also show that this reporter mouse is a useful and powerful tool for obtaining new insights into the pathomechanisms of ALS.

中文翻译：

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CCR2位于ALS小鼠腰脊髓的小胶质细胞和神经元以及浸润的单核细胞中。

表达CCR2的循环单核细胞是否渗透到中枢神经系统（CNS）并有助于肌萎缩性侧索硬化症（ALS）的致病性仍存在争议。先前的报道使用常规的免疫组织化学方法显示，CCR2仅在ALS模型小鼠的脊髓中由星形胶质细胞表达，但不渗透单核细胞/小胶质细胞或神经元。在这项研究中，我们使用CCR2报告基因小鼠（Ccr2rfp / +-Cx3cr1gfp / +-SOD1G93A Tg小鼠）评估了CCR2在ALS小鼠中枢神经系统中的细胞分布，这是一种直接检测CCR2蛋白分布的更复杂的方法。我们发现在疾病进展过程中，CCR2 +单核细胞在腰脊髓中的浸润增加。此外，从疾病中期开始，CCR2部分分布在小胶质细胞和神经元中，但不是星形胶质细胞，与以前的发现形成鲜明对比。这些新颖的观察结果表明，CCR2 +单核细胞浸润由于小胶质细胞和神经元的毒性转化而导致CNS环境恶化，从而形成了神经炎症的恶性循环并导致ALS病理加速。我们的发现还表明，这种报道基因小鼠是获得ALS发病机制新见解的有用而强大的工具。