Macrophages counteract demyelination in a mouse model of globoid cell leukodystrophy.
Macrophages counteract demyelination in a mouse model of globoid cell leukodystrophy.
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DOI：
10.1523/jneurosci.6344-10.2011
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发表时间：
2011-03-09
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影响因子：
--
通讯作者：
Duncan ID
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作者：
Kondo Y;Adams JM;Vanier MT;Duncan ID
小胶质细胞和巨噬细胞在许多神经系统疾病包括脱髓鞘疾病如多发性硬化症和脑白质营养不良中是有益的还是有害的，目前仍在争论中。探讨这个问题是特别感兴趣的球样细胞脑白质营养不良（GLD），遗传性致命的脱髓鞘疾病，因为它在神经系统中的快速进行性脱髓鞘伴随着大量的球形巨噬细胞的特征性积累。因此，我们将真正的GLD模型twitcher（twi）小鼠与巨噬细胞缺陷型骨硬化突变体杂交，并研究了所得的巨噬细胞缺陷型twitcher（twi+op）小鼠。twi+op小鼠在白色物质中具有很少的小胶质细胞和巨噬细胞，并且有趣的是，与twi小鼠相比显示出更严重的临床表型。在45日龄时，twi+op小鼠脊髓中的无髓鞘轴突数量显著高于twi小鼠。这种差异似乎是由于twi+op小鼠的髓鞘再生受损，而不是加速脱髓鞘。定量逆转录PCR和免疫组化研究显示，在twi+op小鼠中，响应脱髓鞘的少突胶质细胞祖细胞的募集受到损害。在twi+op小鼠的白色实质中髓鞘碎片的增加表明巨噬细胞的吞噬作用可能在促进髓鞘再生中起重要作用。巨噬细胞标志物的保护性和破坏性的表型显着上调，在twi小鼠的脊髓，但接近正常的twi+op小鼠由于减少巨噬细胞的数量。巨噬细胞在GLD中的总体作用似乎通过促进髓鞘修复而对髓鞘有益。
Whether microglia and macrophages are beneficial or harmful in many neurological disorders including demyelinating diseases such as multiple sclerosis and the leukodystrophies is currently under debate. Answering this question is of special interest in globoid cell leukodystrophy (GLD), a genetic fatal demyelinating disease, because its rapidly progressive demyelination in the nervous system is accompanied by characteristic accumulation of numerous globoid macrophages. Therefore we cross-bred the twitcher (twi) mouse, a bona-fide model of GLD, with the macrophage-deficient osteopetrotic mutant and studied the resultant macrophage-deficient twitcher (twi+op) mouse. The twi+op mouse had few microglia and macrophages in the white matter and, interestingly, showed a more severe clinical phenotype compared to the twi mouse. The number of non-myelinated axons in the spinal cord was significantly higher in twi+op mice than in twi mice at 45 days old. The difference appeared to be due to impaired remyelination in twi+op mice, rather than accelerated demyelination. Quantitative reverse transcription PCR and immunohistochemical studies revealed that the recruitment of oligodendrocyte progenitor cells in response to demyelination was compromised in twi+op mice. Increased myelin debris in the white matter parenchyma of twi+op mice suggested that phagocytosis by macrophages may play an important role in promoting remyelination. Macrophage markers for both protective and destructive phenotypes were significantly upregulated in the spinal cord of twi mice, but were close to normal in twi+op mice due to the reduced macrophage number. The overall effects of macrophages in GLD appear to be beneficial to myelin by promoting myelin repair.