Chemokines and their receptors in the brain: Pathophysiological roles in ischemic brain injury
Chemokines and their receptors in the brain: Pathophysiological roles in ischemic brain injury
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DOI：
10.1016/j.lfs.2003.09.019
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发表时间：
2003-12-05
期刊：
影响因子：
6.1
通讯作者：
Satoh, M
中科院分区：
文献类型：
--
作者：
Minami, M;Satoh, M
趋化因子是一大类结构相关的小细胞因子，最初被认为是炎症和免疫反应中调节白细胞迁移的因素。趋化因子及其受体在大脑中的产生在各种病理条件下已被报道。我们发现单核细胞趋化蛋白-1 （MCP-1）和巨噬细胞炎症蛋白-1 α (MIP-1 α)的mRNA表达在局灶性脑缺血后的大鼠脑中被诱导，并且脑室内注射病毒性巨噬细胞炎症蛋白- ii (vMIP-II)，一种广谱趋化因子受体拮抗剂，以剂量依赖的方式减少梗死体积。这些发现表明脑趋化因子参与缺血性损伤，趋化因子受体是卒中治疗干预的潜在靶点。另一个抑制趋化因子有害作用的潜在靶点是调节趋化因子产生的信号传递系统。然而，对于缺血脑中趋化因子的产生是如何调节的，我们知之甚少。我们在皮质纹状体切片培养中通过激活NMDA受体检测了兴奋性毒性损伤对MCP-1产生的诱导作用，发现兴奋性毒性损伤诱导了MCP-1在切片培养中的产生。MCP-1的免疫活性几乎全部集中在星形胶质细胞上。另一方面，在富集的星形胶质细胞培养中，NMDA处理未能增加MCP-1的产生，这表明NMDA剂量不直接作用于星形胶质细胞。损伤神经元向星形胶质细胞发送信号，诱导MCP-1的产生。这些结果表明，器官型切片培养有助于研究损伤脑中趋化因子产生的分子机制。(C) 2003 Elsevier Inc.版权所有。
Chemokines constitute a large family of structurally-related small cytokines originally identified as factors regulating the migration of leukocytes in inflammatory and immune responses. Production of chemokines and their receptors in the brain has been reported under various pathological conditions. We revealed that mRNA expression for monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha), members of the CC chemokines, was induced in the rat brain after focal cerebral ischemia, and that intracerebroventricular injection of viral macrophage inflammatory protein-II (vMIP-II), a broad-spectrum chemokine receptor antagonist, reduced infarct volume in a dose-dependent manner. These findings suggest that brain chemokines are involved in ischemic injury, and that chemokine receptors are potential targets for therapeutic intervention in stroke. Another potential target to suppress the harmful effect of chemokines is the signal transmission system(s) regulating the chemokine production. However, very little is known about how the production of chemokines is regulated in the ischemic brain. We examined the induction of MCP-1 production by excitotoxic injury via activation of NMDA receptors in the cortico-striatal slice cultures, and found that excitotoxic injury induced MCP-1 production in the slice culture. Almost all of the MCP-1 immumoreactivity was located on astrocytes. On the other hand, NMDA-treatment failed to increase the MCP-1 production in the enriched astrocyte cultures, indicating that NMDA dose not directly act on astrocytes. Some signal(s) is likely sent from the injured neurons to astrocytes to induce the MCP-1 production. These results showed that organotypic slice cultures are useful to investigate the molecular mechanism regulating the chemokine production in the injured brain. (C) 2003 Elsevier Inc. All rights reserved.