Experimental autoimmune encephalomyelitis repressed by microglial paralysis
Experimental autoimmune encephalomyelitis repressed by microglial paralysis
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DOI：
10.1038/nm1177
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发表时间：
2005-02-01
期刊：
影响因子：
82.9
通讯作者：
Aguzzi, A
中科院分区：
文献类型：
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作者：
Heppner, FL;Greter, M;Aguzzi, A
尽管小胶质细胞活化在炎症性、退行性和肿瘤性中枢神经系统（CNS）疾病中均会发生，但其在发病机制中的作用尚不明确。我们通过培育CD11b - HSVTK转基因小鼠来研究这一问题，该小鼠在巨噬细胞和小胶质细胞中表达单纯疱疹胸苷激酶。更昔洛韦处理源自CD11b - HSVTK小鼠的器官型脑片培养物，可消除小胶质细胞释放的亚硝酸盐、促炎细胞因子和趋化因子。对CD11b - HSVTK小鼠全身给予更昔洛韦会引发造血毒性，而野生型骨髓移植可预防这种毒性。在骨髓嵌合体中，更昔洛韦可阻断轴突切断后面神经核中的小胶质细胞活化，并抑制实验性自身免疫性脑脊髓炎的发展。我们得出结论，小胶质细胞麻痹会抑制炎症性CNS病变的发展和维持。因此，小胶质细胞区室为炎症性CNS疾病提供了一个潜在的治疗靶点。这些结果证实CD11b - HSVTK小鼠是一种研究小胶质细胞活化对体内CNS疾病影响的工具。
Although microglial activation occurs in inflammatory, degenerative and neoplastic central nervous system (CNS) disorders, its role in pathogenesis is unclear. We studied this question by generating CD11b-HSVTK transgenic mice, which express herpes simplex thymidine kinase in macrophages and microglia. Ganciclovir treatment of organotypic brain slice cultures derived from CD11b-HSVTK mice abolished microglial release of nitrite, proinflammatory cytokines and chemokines. Systemic ganciclovir administration to CD11b-HSVTK mice elicited hematopoietic toxicity, which was prevented by transfer of wild-type bone marrow. In bone marrow chimeras, ganciclovir blocked microglial activation in the facial nucleus upon axotomy and repressed the development of experimental autoimmune encephalomyelitis. We conclude that microglial paralysis inhibits the development and maintenance of inflammatory CNS lesions. The microglial compartment thus provides a potential therapeutic target in inflammatory CNS disorders. These results validate CD11b-HSVTK mice as a tool to study the impact of microglial activation on CNS diseases in vivo.