Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination
Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination
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DOI：
10.1093/brain/aws262
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发表时间：
2013-01-01
期刊：
影响因子：
14.5
通讯作者：
Stangel, Martin
中科院分区：
文献类型：
--
作者：
Skripuletz, Thomas;Hackstette, Diane;Stangel, Martin
最近的证据表明，星形胶质细胞在调节多发性硬化的脱髓鞘和髓鞘再生中起重要作用。星形胶质细胞的作用是有争议的，有益和有害的影响正在讨论中。我们进行了功能丧失的基础上的星形胶质细胞耗竭的cuprizone诱导的啮齿动物模型的脱髓鞘的研究。这导致C57 BL/6野生型小鼠中强烈的星形胶质细胞增生，伴随着小胶质细胞增生和脱髓鞘。胶质细胞酸性蛋白-胸苷激酶转基因小鼠星形胶质细胞的消融与受损髓鞘清除失败和髓鞘再生连续延迟有关。尽管少突胶质细胞死亡，髓鞘仍然存在，但超微结构研究表明，髓鞘结构松动，这种受损的髓鞘没有保护轴突。这些改变与小胶质细胞活化减少有关。因此，我们的研究结果表明，星形胶质细胞的损失并不能防止髓鞘损伤，但通过招募小胶质细胞清除受损的髓鞘受损。进一步的研究表明，这一过程是由趋化因子CXCL 10调节的。由于髓鞘碎片的延迟清除，髓鞘再生和少突胶质细胞前体细胞增殖受损。忽略髓鞘碎片影响的实验表明，在髓鞘再生过程中，星形胶质细胞对少突胶质细胞再生有额外的有益作用。总之，这些数据首次在体内证明，星形胶质细胞提供的信号环境，形成了招募小胶质细胞清除髓鞘碎片的基础，这是后续修复机制所需的过程。这对于理解脱髓鞘疾病如多发性硬化症的再生过程非常重要。
Recent evidence suggests that astrocytes play an important role in regulating de- and remyelination in multiple sclerosis. The role of astrocytes is controversial, and both beneficial as well as detrimental effects are being discussed. We performed loss-of-function studies based on astrocyte depletion in a cuprizone-induced rodent model of demyelination. This led to strong astrogliosis accompanied by microgliosis and demyelination in C57BL/6 wild-type mice. Ablation of astrocytes in glial fibrillary acidic protein-thymidine kinase transgenic mice was associated with a failure of damaged myelin removal and a consecutive delay in remyelination. Despite oligodendrocyte death, myelin was still present, but ultrastructual investigations showed that the myelin structure was loosened and this damaged myelin did not protect axons. These alterations were associated with a decrease in microglial activation. Thus, our results show that astrocyte loss does not prevent myelin damage, but clearance of damaged myelin through recruitment of microglia is impaired. Further studies suggest that this process is regulated by the chemokine CXCL10. As a consequence of the delayed removal of myelin debris, remyelination and oligodendrocyte precursor cell proliferation were impaired. Experiments omitting the influence of myelin debris demonstrated an additional beneficial effect of astrocytes on oligodendrocyte regeneration during remyelination. In conclusion, these data demonstrate for the first time in vivo that astrocytes provide the signal environment that forms the basis for the recruitment of microglia to clear myelin debris, a process required for subsequent repair mechanisms. This is of great importance to understanding regenerative processes in demyelinating diseases such as multiple sclerosis.