Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination
Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination
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DOI：
10.1093/brain/awr199
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发表时间：
2011-09-01
期刊：
影响因子：
14.5
通讯作者：
Bethea, John R.
中科院分区：
文献类型：
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作者：
Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
肿瘤坏死因子与包括多发性硬化症在内的多种神经退行性疾病的病理生理学相关。肿瘤坏死因子以两种具有生物活性的形式存在，即可溶性和跨膜形式。在此我们表明，选择性抑制可溶性肿瘤坏死因子在实验性自身免疫性脑脊髓炎中具有治疗作用。用XPro1595（一种选择性可溶性肿瘤坏死因子阻滞剂）治疗可改善临床结果，而用依那西普对两种形式的肿瘤坏死因子进行非选择性抑制则没有保护作用。XPro1595的治疗效果与轴突保护和髓鞘致密性改善相关，同时伴有轴突特异性分子（如神经丝 - H）表达增加以及与轴突损伤相关的非磷酸化神经丝 - H表达减少。经XPro1595治疗的小鼠显示出明显的髓鞘再生，同时伴有髓鞘特异性基因表达升高和少突胶质细胞前体细胞数量增加。对实验性自身免疫性脑脊髓炎后脊髓中肿瘤坏死因子受体的免疫组织化学特征分析表明，肿瘤坏死因子受体1在神经元、少突胶质细胞和星形胶质细胞中表达，而肿瘤坏死因子受体2定位于少突胶质细胞、少突胶质细胞前体细胞、星形胶质细胞和巨噬细胞/小胶质细胞。重要的是，在进行性多发性硬化症患者的尸检脊髓中发现了类似的表达模式，这表明对肿瘤坏死因子受体信号传导的药理学调节可能不仅是影响小鼠实验性自身免疫性脑脊髓炎病程，也是影响人类多发性硬化症的一个重要靶点。总之，我们的数据表明，选择性抑制可溶性肿瘤坏死因子可改善实验性自身免疫性脑脊髓炎后的恢复，并且跨膜肿瘤坏死因子介导的信号传导对于轴突和髓鞘保护以及髓鞘再生至关重要，这为多发性硬化症的治疗开辟了一条新途径。
Tumour necrosis factor is linked to the pathophysiology of various neurodegenerative disorders including multiple sclerosis. Tumour necrosis factor exists in two biologically active forms, soluble and transmembrane. Here we show that selective inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis. Treatment with XPro1595, a selective soluble tumour necrosis factor blocker, improves the clinical outcome, whereas non-selective inhibition of both forms of tumour necrosis factor with etanercept does not result in protection. The therapeutic effect of XPro1595 is associated with axon preservation and improved myelin compaction, paralleled by increased expression of axon-specific molecules (e.g. neurofilament-H) and reduced expression of non-phosphorylated neurofilament-H which is associated with axon damage. XPro1595-treated mice show significant remyelination accompanied by elevated expression of myelin-specific genes and increased numbers of oligodendrocyte precursors. Immunohistochemical characterization of tumour necrosis factor receptors in the spinal cord following experimental autoimmune encephalomyelitis shows tumour necrosis factor receptor 1 expression in neurons, oligodendrocytes and astrocytes, while tumour necrosis factor receptor 2 is localized in oligodendrocytes, oligodendrocyte precursors, astrocytes and macrophages/microglia. Importantly, a similar pattern of expression is found in post-mortem spinal cord of patients affected by progressive multiple sclerosis, suggesting that pharmacological modulation of tumour necrosis factor receptor signalling may represent an important target in affecting not only the course of mouse experimental autoimmune encephalomyelitis but human multiple sclerosis as well. Collectively, our data demonstrate that selective inhibition of soluble tumour necrosis factor improves recovery following experimental autoimmune encephalomyelitis, and that signalling mediated by transmembrane tumour necrosis factor is essential for axon and myelin preservation as well as remyelination, opening the possibility of a new avenue of treatment for multiple sclerosis.