CNS-specific Therapy for Ongoing EAE by Silencing IL-17 Pathway in Astrocytes
CNS-specific Therapy for Ongoing EAE by Silencing IL-17 Pathway in Astrocytes
复制标题
通过沉默星形胶质细胞中的 IL-17 途径治疗持续性 EAE 的 CNS 特异性疗法
DOI：
10.1038/mt.2012.12
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发表时间：
2012-07-01
影响因子：
12.4
通讯作者：
Zhang, Guang-Xian
中科院分区：
文献类型：
--
作者：
Yan, Yaping;Ding, Xiaoli;Zhang, Guang-Xian
白介素17(IL-17)细胞因子家族在多发性硬化症(MS)动物模型实验性自身免疫性脑脊髓炎(EAE)的进展中起着至关重要的作用。一项针对神经外胚层的基因敲除研究表明，星形胶质细胞限制性消融Act1可以改善EAE。Act1是IL-17家族成员(IL-17A、IL-17F和IL-17C)介导的关键和常见的信号转录因子。然而，星形胶质细胞ACT1缺乏对正在进行的疾病的影响，这对MS治疗具有临床意义，尚未被研究。在这里我们报告脑室内(I.C.V.)注射新型慢病毒载体(ShAct1)在星形胶质细胞中下调Act1的表达，有效地抑制了EAE诱导、临床发病和疾病高峰期(持续阶段)的疾病进展，显著减少了中枢神经系统(CNS)中浸润性炎症细胞的数量和Th17细胞的百分比。这主要是由于Th17相关趋化因子在星形胶质细胞中的表达受到抑制，而中枢神经系统的神经营养因子和外周的免疫反应没有受到影响。这些结果表明，阻断星形胶质细胞中的IL-17通路是一种有前景的治疗多发性硬化的方法，具有中枢神经系统特异性，不会干扰系统免疫反应，这是传统多发性硬化症治疗中的主要问题。2017年8月25日收到；2012年1月18日接受；2012年3月20日在线预发。DOI：10.1038/mt.2012.12
The interleukin-17 (IL-17) cytokine family is crucial to the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). It has been shown in a neuroectoderm-specific knockout study that astrocyte-restricted ablation of Act1, a key and common transcription factor for signals mediated by IL-17 family members (IL-17A, IL-17F, and IL-17C), ameliorates EAE. However, the effect of Act1 deficiency in astrocytes on ongoing disease, which is of clinical relevance for MS therapy, has not been investigated. Here we report that intracerebroventricular (i.c.v.) injection of a novel lentiviral vector (shAct1) to knockdown Act1 expression in astrocytes effectively inhibited disease progression at EAE induction, clinical onset, and peak of disease (ongoing phases), with significantly reduced numbers of infiltrating inflammatory cells and percentage of Th17 cells in the central nervous system (CNS). This was mainly due to the suppressed expression of Th17-related chemokines in astrocytes, while neurotrophic factors in the CNS and immune responses in the periphery were not affected. These results demonstrate that blocking the IL-17 pathways in astrocytes is a promising therapeutic approach for MS in a CNS-specific manner, which does not interfere with systemic immune responses, a major concern in conventional MS therapy. Received 25 August 2017; accepted 18 January 2012; advance online publication 20 March 2012. doi:10.1038/mt.2012.12