Molecular signature of slowly expanding lesions in progressive multiple sclerosis
Molecular signature of slowly expanding lesions in progressive multiple sclerosis
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DOI：
10.1093/brain/awaa158
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发表时间：
2020-07-01
期刊：
影响因子：
14.5
通讯作者：
Brueck, Wolfgang
中科院分区：
文献类型：
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作者：
Jaeckle, Katharina;Zeis, Thomas;Brueck, Wolfgang
多发性硬化症是一种免疫介导的中枢神经系统慢性炎症性疾病，可导致灰质和白质脱髓鞘病变。在复发缓解期，炎症性、活动性脱髓鞘白质病变占主导地位，而在进展期，所谓的缓慢扩张病变是特征性的。这些病变显示巨噬细胞/小胶质细胞在其边界积聚，介导髓磷脂的持续破坏和轴突变性。慢性多发性硬化症病变进展的确切发病机制尚不清楚。在本研究中，我们对13名年龄在30至74岁之间（5名女性和8名男性）的缓慢扩张病变（n = 21）进行了详细的免疫学和分子分析，重点关注巨噬细胞/小胶质细胞分化。通过应用小胶质细胞特异性标记TMEM119，我们证明在病变边缘积聚的细胞几乎完全属于小胶质细胞谱系。巨噬细胞/小胶质细胞可细分为与炎症和退行性过程相关的M1型和具有保护特性的M2型，因此也可以观察到中间极化表型。通过使用一组表征M1型或m2型巨噬细胞/小胶质细胞的标志物，我们观察到M1型分化细胞在病变边缘优先积累，表明这些细胞在病变进展中起关键作用。此外，对缓慢扩张和慢性非活动病变以及正常白质的大解剖病变边缘进行了无偏倚的RNA微阵列分析。在缓慢扩张的病变中，我们共鉴定出165个基因上调，35个基因下调。上调的基因包括参与免疫防御和炎症过程的巨噬细胞/小胶质细胞相关基因。上调的基因包括ALOX15B、MME和TNFRSF25。我们通过定量PCR证实ALOX15B的表达增加，免疫组织化学证实这三个基因在蛋白水平上的表达增加。总之，本研究详细描述了进展性多发性硬化症病变缓慢扩张的特征，并证明了病变边缘具有M1分化的常驻小胶质细胞的优先积累。微阵列分析显示，与免疫功能、代谢过程以及转录/翻译相关的基因表达增加。因此，这些基因可能作为未来的治疗靶点，以阻止病变进展。
Multiple sclerosis is an immune-mediated chronic inflammatory disease of the CNS that leads to demyelinated lesions in the grey and white matter. Inflammatory, active demyelinating white matter lesions predominate in the relapsing-remitting disease stages, whereas in the progressive stage the so-called slowly expanding lesion is characteristic. These lesions show an accumulation of macrophages/microglia at their borders, mediating the ongoing myelin breakdown and axonal degeneration. The exact pathogenetic mechanisms of lesion progression in chronic multiple sclerosis are still not clear. In the present study, we performed a detailed immunological and molecular profiling of slowly expanding lesions (n = 21) from 13 patients aged between 30 to 74 years (five females and eight males), focusing on macrophage/microglia differentiation. By applying the microglia-specific marker TMEM119, we demonstrate that cells accumulating at the lesion edge almost exclusively belonged to the microglia lineage. Macrophages/microglia can be subdivided into the M1 type, which are associated with inflammatory and degenerative processes, and M2 type, with protective properties, whereby also intermediate polarization phenotypes can be observed. By using a panel of markers characterizing M1- or M2-type macrophages/microglia, we observed a preferential accumulation of M1-type differentiated cells at the lesion edge, indicating a crucial role of these cells in lesion progression. Additionally, unbiased RNA microarray analyses of macrodissected lesion edges from slowly expanding and chronic inactive lesions as well as normal-appearing white matter were performed. In slowly expanding lesions, we identified a total of 165 genes that were upregulated and 35 genes that were downregulated. The upregulated genes included macrophage/microglia-associated genes involved in immune defence and inflammatory processes. Among the upregulated genes were ALOX15B, MME and TNFRSF25. We confirmed increased expression of ALOX15B by quantitative PCR, and of all three genes on the protein level by immunohistochemistry. In conclusion, the present study characterized in detail slowly expanding lesions in progressive multiple sclerosis and demonstrated a preferential accumulation of resident microglia with M1 differentiation at the lesion edge. Microarray analysis showed an increased expression of genes related to immune function, metabolic processes as well as transcription/translation. Thus, these genes may serve as future therapeutic targets to impede lesion progression.