Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity:: role of TNF-α
Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity:: role of TNF-α
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DOI：
10.1096/fj.05-5106com
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发表时间：
2006-04-01
期刊：
影响因子：
4.8
通讯作者：
O'Callaghan, James P.
中科院分区：
文献类型：
--
作者：
Sriram, Krishnan;Matheson, Joanna M.;O'Callaghan, James P.
肿瘤坏死因子-α的高表达与疾病、创伤和化学诱导的神经变性的神经病理效应有关。在此之前，我们已经证明，肿瘤坏死因子受体的缺乏对MPTP诱导的纹状体多巴胺能神经毒性具有保护作用，这一发现暗示了肿瘤坏死因子-α在神经退行性变中的作用。在这里，我们证明了肿瘤坏死因子受体的缺乏抑制了小胶质细胞的激活，并改变了大脑区域对MPTP的敏感性。MPTP诱导的小胶质细胞衍生因子，如肿瘤坏死因子-α、单核细胞趋化蛋白-1和白介素1-α的表达，先于纹状体多巴胺能神经末梢的退化和星形胶质细胞增生症，通过纹状体多巴胺和TH的丢失以及纹状体GFAP的增加来评估。多巴胺再摄取抑制剂诺米芬辛的药理神经保护作用可消除纹状体多巴胺能神经毒性和相关的小胶质细胞激活。同样，在缺乏肿瘤坏死因子受体的小鼠中，小胶质细胞的激活受到抑制，这一发现与肿瘤坏死因子-α在纹状体MPTP神经毒性中的作用一致。然而，在海马区，肿瘤坏死因子受体缺陷小鼠显示MPTP后神经元损伤加剧，荧光Jade-B染色(用于识别变性神经元)和微管相关蛋白-2(MAP-2)免疫反应性降低。这些效应并不伴随着小胶质细胞的激活，而是与氧化应激(酪氨酸残基的亚硝化)有关。这些发现表明，肿瘤坏死因子-α在海马区具有神经营养/神经保护作用。我们观察到的小胶质细胞和小胶质细胞相关因子在区域密度、分布和/或活性上的显著差异可能会影响这种细胞类型的区域特异性作用。综上所述，我们的结果表明，肿瘤坏死因子-α在大脑中具有区域特异性和双重作用：纹状体神经变性的促进者和海马区神经变性的保护者。--Sriram，K.，Matheon，J.M.，Benkovic，S.A.，Miller，D.B.，Luster，M.I.，O‘Callaghan，J.P.缺乏肿瘤坏死因子受体抑制小胶质细胞的激活并改变大脑区域对MPTP引起的神经毒性的敏感性：肿瘤坏死因子-α的作用。
Enhanced expression of tumor necrosis factor ( TNF)-alpha, is associated with the neuropathological effects underlying disease-, trauma- and chemically induced neurodegeneration. Previously, we have shown that deficiency of TNF receptors protects against MPTP-induced striatal dopaminergic neurotoxicity, findings suggestive of a role for TNF-alpha in neurodegeneration. Here, we demonstrate that deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP. MPTP-induced expression of microglia-derived factors, TNF-alpha, MCP-1, and IL-1 alpha, preceded the degeneration of striatal dopaminergic nerve terminals and astrogliosis, as assessed by loss of striatal dopamine and TH, and an increase in striatal GFAP. Pharmacological neuroprotection with the dopamine reuptake inhibitor, nomifensine, abolished striatal dopaminergic neurotoxicity and associated microglial activation. Similarly, in mice lacking TNF receptors, microglial activation was suppressed, findings consistent with a role for TNF-alpha in striatal MPTP neurotoxicity. In the hippocampus, however, TNF receptor-deficient mice showed exacerbated neuronal damage after MPTP, as evidenced by Fluoro Jade-B staining (to identify degenerating neurons) and decreased microtubule-associated protein-2 (MAP-2) immunoreactivity. These effects were not accompanied by microglial activation, but were associated with increased oxidative stress (nitrosylation of tyrosine residues). These findings suggest that TNF-alpha exerts a neurotrophic/ neuroprotective effect in hippocampus. The marked differences we observed in the regional density, distribution and/or activity of microglia and microgliaderived factors may influence the region-specific role for this cell type. Taken together, our results are indicative of a region-specific and dual role for TNF-alpha in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus. -Sriram, K., Matheson, J.M., Benkovic, S. A., Miller, D. B., Luster, M. I., O'Callaghan, J. P. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP- induced neurotoxicity: role of TNF-alpha.