Activation of Interferon Signaling Pathways in Spinal Cord Astrocytes from an ALS Mouse Model
Activation of Interferon Signaling Pathways in Spinal Cord Astrocytes from an ALS Mouse Model
复制标题
DOI：
10.1002/glia.21167
复制
发表时间：
2011-06-01
期刊：
影响因子：
6.2
通讯作者：
Zhang, Dongxian
中科院分区：
文献类型：
--
作者：
Wang, Rengang;Yang, Bo;Zhang, Dongxian
肌萎缩性侧索硬化症（ALS）是一种主要影响运动神经元的进行性神经退行性疾病。最近的研究表明，ALS的疾病进展是非细胞自主的，尽管不同疾病阶段神经元和神经胶质细胞之间的相互作用尚不完全清楚。在这里，我们证明干扰素（IFN）信号通路在人类SOD1（G93A）转基因小鼠（ALS啮齿动物模型）中被激活。症状前年龄SOD1（G93A）小鼠脊髓中ifn刺激基因（ISGs）增加。此外，在运动神经元周围的星形胶质细胞中发现了上调的isg及其转录激活因子，这表明星形胶质细胞中的IFN信号是由运动神经元的特异性病理变化触发的。此外，培养的星形胶质细胞诱导isg对IFN，特别是I型IFN高度敏感。星形胶质细胞内的isg在体外被内质网应激诱导的神经变性特异性激活，暗示在SOD1突变小鼠的症状前阶段也有类似的过程。最后，IFN α受体1的减少或缺失抑制了IFN信号传导，延长了SOD1（G93A）小鼠的寿命。因此，IFN信号通路的激活代表了运动神经元和星形胶质细胞之间对ALS病理变化的早期“对话”。(C) 2011 Wiley-Liss, Inc。
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting predominantly motor neurons. Recent studies suggest that the disease progression of ALS is non-cell-autonomous, although the interaction between neurons and glial cells in different disease stages is not entirely clear. Here, we demonstrate that the interferon (IFN) signaling pathway is activated in human SOD1(G93A) transgenic mice, a rodent model of ALS. IFN-stimulated genes (ISGs) increased in the spinal cord of SOD1(G93A) mice at a presymptomatic age. In addition, the up-regulated ISGs, and most likely their transcriptional activators, were found specifically in astrocytes surrounding motor neurons, suggesting that IFN signaling in astrocytes was triggered by specific pathologic changes in motor neurons. Furthermore, induction of ISGs in cultured astrocytes was highly sensitive to IFN, especially Type I IFN. ISGs in astrocytes were activated specifically by endoplasmic reticulum stress-induced neurodegeneration in vitro, implicating a similar process in the presymptomatic stage of SOD1 mutant mice. Finally, reduction or deletion of IFN alpha receptor 1 inhibited IFN signaling and increased the life-span of SOD1(G93A) mice. Thus, the activation of IFN signaling pathways represents an early "dialogue" between motor neurons and astrocytes in response to pathological changes in ALS. (C) 2011 Wiley-Liss, Inc.