Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection
Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection
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DOI：
10.1093/brain/awm291
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发表时间：
2008-01-01
期刊：
影响因子：
14.5
通讯作者：
Schaeren-Wiemers, Nicole
中科院分区：
文献类型：
--
作者：
Zeis, Thomas;Graumann, Ursula;Schaeren-Wiemers, Nicole
多发性硬化症是一种慢性中枢神经系统炎症性疾病。尽管进行性轴突损伤和弥漫性炎症损伤已在该疾病的慢性期表现出来，但对这些病理过程的分子机制知之甚少。为了确定这些机制，我们研究了非病变组织中的基因表达谱，即所谓的正常外观白质（NAWM）。我们对11例多发性硬化症患者和8例对照患者的皮质下白质进行了差异基因表达分析和定量RT-PCR。通过原位杂交和免疫荧光研究进一步详细分析差异表达基因。我们发现，已知参与抗炎和保护机制的基因，如STAT6、JAK1、IL-4R、IL-10、铬粒蛋白C和Hif-1在多发性硬化症NAWM中持续上调。另一方面，参与促炎机制的基因，如STAT4、IL-1和MCSF，也上调，但不太规律。免疫荧光共定位分析显示，STAT6、JAK1、IL-4R和IL-13R主要在少突胶质细胞中表达，而STAT4主要在小胶质细胞中表达。与这些数据一致，原位杂交分析显示，在多发性硬化NAWM中，HIF-1在少突胶质细胞中表达增加，HLA-DR在小胶质细胞中表达增加。多发性硬化病例间STAT6、JAK1、JAK3和IL-4R表达水平的一致性提示少突胶质细胞中STAT6信号通路的整体激活，而STAT4和HLA-DR的表达提示小胶质细胞中促炎通路的激活。少突胶质细胞驱动的参与抗炎机制的基因上调可能保护中枢神经系统环境，从而限制病变的形成，而小胶质细胞中促炎机制的激活可能有利于疾病的进展。总之，我们的数据表明，在多发性硬化症的整个脑白质中存在内源性炎症反应，其中少突胶质细胞积极参与。这种反应可能进一步影响并在一定程度上促进病变的形成。
Multiple sclerosis is a chronic inflammatory disease of the CNS. Although progressive axonal injury and diffuse inflammatory damage has been shown in the chronic phase of the disease, little is known about the molecular mechanisms underlying these pathological processes. In order to identify these mechanisms, we have studied the gene expression profile in non-lesion containing tissue, the so-called normal-appearing white matter (NAWM). We performed differential gene expression analysis and quantitative RT-PCR on subcortical white matter from 11 multiple sclerosis and 8 control cases. Differentially expressed genes were further analysed in detail by in situ hybridization and immunofluorescence studies. We show that genes known to be involved in anti-inflammatory and protective mechanisms such as STAT6, JAK1, IL-4R, IL-10, Chromogranin C and Hif-1 are consistently upregulated in the multiple sclerosis NAWM. On the other hand, genes involved in pro-inflammatory mechanisms, such as STAT4, IL-1 and MCSF, were also upregulated but less regularly. Immunofluorescence colocalization analysis revealed expression of STAT6, JAK1, IL-4R and IL-13R mainly in oligodendrocytes, whereas STAT4 expression was detected predominantly in microglia. In line with these data, in situ hybridization analysis showed an increased expression in multiple sclerosis NAWM of HIF-1 in oligodendrocytes and HLA-DR in microglia cells. The consistency of the expression levels of STAT6, JAK1, JAK3 and IL-4R between the multiple sclerosis cases suggests an overall activation of the STAT6-signalling pathway in oligodendrocytes, whereas the expression of STAT4 and HLA-DR indicates the activation of pro-inflammatory pathways in microglia. The upregulation of genes involved in anti-inflammatory mechanisms driven by oligodendrocytes may protect the CNS environment and thus limit lesion formation, whereas the activation of pro-inflammatory mechanisms in microglia may favour disease progression. Altogether, our data suggests an endogenous inflammatory reaction throughout the whole white matter of multiple sclerosis brain, in which oligodendrocytes actively participate. This reaction might further influence and to some extent facilitate lesion formation.