Okazaki Rentaro, Doi Toru, Hayakawa Kentaro, Morioka Kazuhito, Imamura Osamu, Takishima Kunio, Hamanoue Makoto, Sawada Yasuhiro, Nagao Motoshi, Tanaka Sakae, Ogata Toru
Department of Rehabilitation for Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, 4-1 Namiki, Tokorozawa, Saitama, 359-8555, Japan.
Department of Orthopaedic Surgery, The University of Tokyo, 3-7-1, Hongo, Bunkyo-ku, Tokyo, Japan.
J Neuroinflammation. 2016 Sep 5;13(1):235. doi: 10.1186/s12974-016-0690-8.
Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation.
We used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes.
First, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3-4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2.
Our results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases.
脑部炎症是脱髓鞘疾病（如多发性硬化症）的关键组成部分。尽管免疫细胞产生细胞因子和趋化因子引发炎症过程已得到充分表征，但脱髓鞘疾病炎症加重的过程仍不清楚。在此，我们研究了细胞外信号调节激酶异构体之一的Erk2对脱髓鞘炎症的作用。
我们使用了铜螯合剂诱导的脱髓鞘小鼠模型。为了研究Erk2的作用，我们使用了由Nestin-cre驱动的Erk2基因敲除小鼠。我们还建立了小胶质细胞或星形胶质细胞的原代培养，以揭示两种细胞类型之间的相互作用，并确定Erk2在星形胶质细胞中的下游级联反应。
首先，我们发现在脱髓鞘高峰（开始喂食铜螯合剂4周后）之前，胼胝体内的星形胶质细胞中Erk特别活化。然后，我们发现在我们的模型中，通过旋转棒试验测量，从神经细胞中基因敲除Erk2可显著保留髓鞘结构和运动功能。虽然在Erk2基因敲除小鼠中，小胶质细胞的初始活化没有改变，但这些小鼠在模型第3至4周时炎症介质的表达降低。此外，随后以小胶质细胞和反应性星形胶质细胞积聚为特征的炎症性胶质细胞反应在Erk2基因敲除小鼠中显著减弱。这些数据表明，星形胶质细胞中的Erk2参与炎症增强和胶质细胞增生。我们还发现，活化的原代培养小胶质细胞可诱导原代培养星形胶质细胞中Erk2活化，并随后产生炎症介质，如Ccl-2。
我们的结果表明，星形胶质细胞中Erk2的活化通过诱导炎症介质和胶质细胞增生，在加重脱髓鞘炎症中起关键作用。因此，针对胶质细胞中Erk2功能的疗法可能是治疗不同脱髓鞘疾病的一种有前途的方法。
