CXCL10 Triggers Early Microglial Activation in the Cuprizone Model
CXCL10 Triggers Early Microglial Activation in the Cuprizone Model
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DOI：
10.4049/jimmunol.1401459
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发表时间：
2015-04-01
影响因子：
4.4
通讯作者：
Kipp, Markus
中科院分区：
文献类型：
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作者：
Clarner, Tim;Janssen, Katharina;Kipp, Markus
广泛的疾病以髓鞘异常和/或少突胶质细胞病理为特征。在大多数（如果不是全部）这些疾病中，发生小胶质细胞的早期激活。然而，我们关于触发早期小胶质细胞激活的因素的知识是不完整的。在这项研究中，我们使用cuprizone模型来研究少突胶质细胞凋亡和早期小胶质细胞激活的时间和因果关系。全基因组基因表达研究揭示了不同的趋化因子的诱导，其中Cxcl 10，Ccl 2和Ccl 3在cuprizone介导的少突胶质细胞凋亡。在CCL 2和CCL 3缺陷敲除小鼠中，早期小胶质细胞活化没有变化，但在CXCL 10缺陷小鼠中显著减少，导致在以后的时间点铜腙毒性的改善。随后的体外实验表明，重组CXCL 10诱导迁移和促炎表型在培养的小胶质细胞，而不影响其吞噬活性或增殖。原位杂交分析表明，Cxcl 10的mRNA主要表达的星形胶质细胞，但也少突胶质细胞，在短期的cuprizone暴露的小鼠。我们的研究结果表明，CXCL 10积极参与小胶质细胞激活的启动。这些发现对CXCL 10在与少突胶质细胞病理学相关的神经炎症过程的启动过程中作为重要介质的作用具有影响。
A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.