Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Glia. 2011 Jan;59(1):166-76. doi: 10.1002/glia.21088.
Reactive astrocytosis, involving activation, hypertrophy, and proliferation of astrocytes, is a characteristic response to inflammation or injury of the central nervous system. We have investigated whether inhibition of reactive astrocytosis influences established experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We made use of transgenic mice, which express herpes simplex virus-derived thymidine kinase under control of a glial fibrillary acidic protein promotor (GFAP HSV-TK mice). Treatment of these mice with ganciclovir leads to inhibition of reactive astrocytosis. When GFAP HSV-TK mice were treated for seven days following onset of EAE with ganciclovir, disease severity increased. Although aquaporin-4 staining on astrocyte endfeet at the glia limitans remained equally detectable, GFAP immunoreactivity and mRNA expression in CNS were reduced by this treatment. Ganciclovir-treated GFAP HSV-TK mice with EAE had a 78% increase in the total number of infiltrating myeloid cells (mainly macrophages), whereas we did not find an increase in infiltrating T cells, using quantitative flow cytometry. Per cell expression of mRNA for the macrophage-associated molecules TNFα, MMP-12 and TIMP-1 was elevated in spinal cord of GFAP HSV-TK mice treated with ganciclovir. Relative expression of CD3ε was downregulated, and expression levels of IFNγ, IL-4, IL-10, IL-17, and Foxp3 were not significantly changed. mRNA expression of CCL2 was upregulated, and CXL10 was downregulated. Thus, inhibition of reactive astrocytosis after initiation of EAE leads to increased macrophage, but not T cell, infiltration, and enhanced severity of EAE. This emphasizes the role of astrocytes in controlling leukocyte infiltration in neuroinflammation.
反应性星形胶质细胞增生，涉及星形胶质细胞的激活、肥大和增殖，是中枢神经系统炎症或损伤的特征性反应。我们研究了抑制反应性星形胶质细胞增生是否会影响实验性自身免疫性脑脊髓炎（EAE），即多发性硬化症的动物模型。我们利用表达单纯疱疹病毒衍生的胸苷激酶的转基因小鼠，该基因受神经胶质纤维酸性蛋白启动子（GFAP HSV-TK 小鼠）的控制。用更昔洛韦治疗这些小鼠可抑制反应性星形胶质细胞增生。当 GFAP HSV-TK 小鼠在 EAE 发病后七天开始用更昔洛韦治疗时，疾病严重程度增加。尽管神经胶质界膜上星形胶质细胞足突的水通道蛋白-4染色仍然同样可检测到，但这种治疗方法降低了中枢神经系统中的 GFAP 免疫反应性和 mRNA 表达。用更昔洛韦治疗的患有 EAE 的 GFAP HSV-TK 小鼠，浸润性髓样细胞（主要为巨噬细胞）总数增加了 78%，而我们通过定量流式细胞术未发现浸润性 T 细胞增加。用更昔洛韦治疗的 GFAP HSV-TK 小鼠脊髓中与巨噬细胞相关的分子 TNFα、MMP-12 和 TIMP-1 的 mRNA 表达升高。相对 CD3ε 的表达下调，IFNγ、IL-4、IL-10、IL-17 和 Foxp3 的表达水平没有明显变化。CCL2 的 mRNA 表达上调，CXL10 的表达下调。因此，在 EAE 发作后抑制反应性星形胶质细胞增生会导致巨噬细胞浸润增加，但 T 细胞浸润没有增加，EAE 的严重程度增加。这强调了星形胶质细胞在控制神经炎症中白细胞浸润中的作用。
