MACROPHAGE RECRUITMENT IN NERVOUS SYSTEM INJURY & REPAIR

神经系统损伤中的巨噬细胞募集

• 批准号: 6165536
• 负责人: JOHN W GRIFFIN
• 金额: $ 17.69万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6165536
• 关键词: axon; cellular immunity; cytokine receptors; gene targeting; genetically modified animals; immunosuppression; laboratory mouse; macrophage; macrophage activating factor; microglia; monocyte; monocyte chemoattractant protein 1; myelin; nerve injury; nervous system regeneration; oligodendroglia; optic nerve; peripheral nervous system; transfection; wallerian degeneration

During nerve fiber degeneration in the peripheral nervous system monocytes are promptly, abundantly, and selectively recruited from the circulation, myelin debris is rapidly cleared, and, presumably in part as a result of macrophage contributions, regeneration (in the rodent) is rapid and extensive. In contrast, during fiber degeneration in the central nervous system (CNS) hematogenous monocytes fail to be recruited, and CNS myelin debris, known to be inimical to axonal outgrowth, is cleared very slowly. Several lines of evidence have raised the possibility that the presence of macrophages within degenerating CNS pathways might increase the likelihood of successful axonal elongation. Recent data from the Griffin and Ransohoff labs suggest that a product of denervated Schwann cells, the C-C chemokine, monocyte chemoattractant protein-1 (MCP-1), provides one important mechanism. The overall goals of this project are: To understand fully the mechanism(s) by which monocytes are recruited into the degenerating PNS and to develop preparations that fail to recruit macrophages during Wallerian degeneration, focusing initially on the hypothesis that activation of the MCP-1 receptor CCR2 is necessary and sufficient to recruit hematogenous monocytes; and to test the hypothesis that providing the degenerating CNS with the capability to recruit circulating monocytes will result in prompt clearance of myelin debris and increased axonal regeneration. The planned studies will characterize the chemokine profiles produced by Schwann cells during Wallerian degeneration, and determine whether MCP-1 and CCR2 knockouts are unable to recruit macrophages normally. We will test a widely cited hypothesis, that complement activation occurs on PNS myelin during Wallerian degeneration, so that complement activation products are chemotropic to macrophages. The final series of experiments will characterize chemokine production and macrophage recruitment in the dorsal columns and the optic nerves of normal mice during Wallerian degeneration, and compare the results to those in transgenic mice in which MCP-1 expression is governed by the GFAP promotor. We anticipate that abundant macrophage recruitment will be seen during CNS fiber degeneration in these animals, and that CNS myelin debris will be rapidly cleared. Such animals will provide the ideal system in which to test the possibility that CNS regeneration will be substantially improved by permitting macrophage recruitment.

在周围神经系统中的神经纤维变性过程中，单核细胞迅速，丰富，有选择地从循环中募集，髓鞘碎片迅速清除，大概是由于巨噬细胞的贡献，重新生成（在啮齿动物中）迅速而广泛。相反，在中枢神经系统（CNS）的纤维变性期间，血源性单核细胞无法募集，并且CNS髓磷脂碎屑（已知对轴突出生的生长都存在），非常缓慢地清除。几条证据提出了一种可能性，即退化的CNS途径中巨噬细胞的存在可能会增加成功的轴突伸长的可能性。 Griffin和Ransohoff Labs的最新数据表明，雪旺细胞的产物C-C趋化因子，单核细胞趋化剂蛋白-1（MCP-1）提供了一种重要机制。该项目的总体目标是：完全了解单核细胞被招募到退化的PNS中的机制，并开发在沃勒式退化过程中未能募集巨噬细胞的制剂，最初集中在MCP-1受体CCR2的激活上，足以使MCP-1受体CCR2足以招募招募和募集疾病的单型血液囊肿；并检验假设，即提供退化的中枢神经系统具有募集循环单核细胞的能力，将迅速清除髓磷脂碎屑并增加轴突再生。计划的研究将表征Schwann细胞在Wallerian变性过程中产生的趋化因子谱，并确定MCP-1和CCR2敲除是否正常募集巨噬细胞。我们将检验一个被广泛引用的假设，即在沃勒（Wallerian）变性期间，PNS髓鞘上的补体激活发生，因此补体激活产物对巨噬细胞趋化。最后一系列的实验将表征在沃勒式变性过程中背侧柱中的趋化因子产生和巨噬细胞募集，以及正常小鼠的视神经，并将结果与​​MCP-1表达的转基因小鼠的结果进行比较，其中MCP-1表达受GFAP促进子的控制。我们预计，在这些动物的CNS纤维变性期间，将会看到大量的巨噬细胞募集，并且CNS髓磷脂碎屑将迅速清除。这样的动物将提供理想的系统，以测试通过允许巨噬细胞募集来大大改善中枢神经系统再生的可能性。