Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation
Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation
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DOI：
10.1016/j.expneurol.2010.04.020
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发表时间：
2010-08-01
影响因子：
5.3
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
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作者：
Mukaino, Masahiko;Nakamura, Masaya;Okano, Hideyuki
我们先前报道了脊髓损伤（SCI）后立即给予抗小鼠IL-6受体抗体（MR 16 -1）的有益效果。本研究的目的是阐明MR 16 -1改善SCI后运动功能的机制。使用流式细胞术对炎症细胞进行定量分析，并使用通过移植遗传标记的纯化造血干细胞产生的骨髓嵌合小鼠进行免疫组化，结果显示，MR 16 -1显着改变了创伤后炎症的中心参与者，从造血巨噬细胞到常驻小胶质细胞。这种变化伴随着受损脊髓内相关细胞因子表达的改变;招募趋化因子（包括CCL 2、CCL 5和CXCL 10）的表达减少，而粒细胞/巨噬细胞集落刺激因子（GM-CSF）（一种已知的小胶质细胞有丝分裂原）的表达增加。我们还发现，常驻小胶质细胞表达的吞噬细胞标记物的水平高于血原性巨噬细胞。与这些发现一致，我们观察到通过MR 16 -1治疗显著降低的组织损伤和降低的髓鞘碎片和轴突生长抑制剂Nogo-A水平。此外，我们观察到在MR 16 -1处理的小鼠中轴突再生和/或发芽增加。我们的研究结果表明，MR 16 -1引起的功能改善涉及小胶质细胞的功能，并提供了新的见解IL-6信号在SCI的病理作用。(C)2010年爱思唯尔公司All rights reserved.
We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI. (C) 2010 Elsevier Inc. All rights reserved.