Inhibition of astroglial NF-κB enhances oligodendrogenesis following spinal cord injury.
Inhibition of astroglial NF-κB enhances oligodendrogenesis following spinal cord injury.
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DOI：
10.1186/1742-2094-10-92
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发表时间：
2013-07-23
影响因子：
9.3
通讯作者：
Bethea JR
中科院分区：
文献类型：
--
作者：
Bracchi-Ricard V;Lambertsen KL;Ricard J;Nathanson L;Karmally S;Johnstone J;Ellman DG;Frydel B;McTigue DM;Bethea JR
星形胶质细胞在神经创伤和神经系统疾病中占据中心地位，因为它们似乎在与这些疾病相关的炎症过程中起主导作用。在此之前，我们报道了利用转基因小鼠模型（gmap - i -κB α-dn小鼠）抑制星形胶质细胞中NF-κB的激活，可以改善脊髓损伤（SCI）后的功能恢复，增加白质保存和轴突保留。在本研究中，我们试图确定这种由于抑制星形胶质细胞中NF-κB活化而产生的改善是否可能是转基因小鼠少突胶质细胞形成增强的结果。为了评估gfap - i - κ b α-dn与野生型（WT）同窝小鼠在脊髓损伤后的少突胶质发生情况，我们使用了溴脱氧尿苷标记、细胞特异性免疫组织化学、共聚焦显微镜和定量细胞计数。为了进一步了解导致白质增加的潜在分子机制，我们对gfap - i - κ b α-dn和WT幼崽小鼠在naïve和脊髓损伤后3天、3天和6周进行了微阵列分析。与脊髓损伤的WT小鼠相比，gfap - i -κB α-dn小鼠星形胶质细胞NF-κB的抑制导致脊髓损伤后6周少突胶质发生增强，并与髓磷脂蛋白脂蛋白水平升高有关。微阵列数据显示，WT和转基因小鼠之间存在大量参与炎症和免疫反应的差异表达基因。我们没有发现浸润脊髓的小胶质细胞/白细胞的数量有任何差异，但确实发现它们的toll样受体4的表达水平有差异。我们还发现在转基因小鼠中，趋化因子受体CXCR4在少突胶质细胞祖细胞和成熟少突胶质细胞上的表达增加。最后，与WT相比，转基因小鼠损伤后TNF受体2水平显著升高。这些研究表明，阻断NF-κB在星形胶质细胞中的有益作用之一是通过改变炎症环境来促进少突胶质细胞的形成。
Astrocytes are taking the center stage in neurotrauma and neurological diseases as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting NF-κB activation in astrocytes, using a transgenic mouse model (GFAP-IκBα-dn mice), results in improved functional recovery, increased white matter preservation and axonal sparing following spinal cord injury (SCI). In the present study, we sought to determine whether this improvement, due to inhibiting NF-κB activation in astrocytes, could be the result of enhanced oligodendrogenesis in our transgenic mice. To assess oligodendrogenesis in GFAP-IκBα-dn compared to wild-type (WT) littermate mice following SCI, we used bromodeoxyuridine labeling along with cell-specific immuno-histochemistry, confocal microscopy and quantitative cell counts. To further gain insight into the underlying molecular mechanisms leading to increased white matter, we performed a microarray analysis in naïve and 3 days, 3 and 6 weeks following SCI in GFAP-IκBα-dn and WT littermate mice. Inhibition of astroglial NF-κB in GFAP-IκBα-dn mice resulted in enhanced oligodendrogenesis 6 weeks following SCI and was associated with increased levels of myelin proteolipid protein compared to spinal cord injured WT mice. The microarray data showed a large number of differentially expressed genes involved in inflammatory and immune response between WT and transgenic mice. We did not find any difference in the number of microglia/leukocytes infiltrating the spinal cord but did find differences in their level of expression of toll-like receptor 4. We also found increased expression of the chemokine receptor CXCR4 on oligodendrocyte progenitor cells and mature oligodendrocytes in the transgenic mice. Finally TNF receptor 2 levels were significantly higher in the transgenic mice compared to WT following injury. These studies suggest that one of the beneficial roles of blocking NF-κB in astrocytes is to promote oligodendrogenesis through alteration of the inflammatory environment.
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影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
影响因子：
14.5
作者：
Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
通讯作者：
Bethea, John R.
影响因子：
11.2
作者：
Goettle, Peter;Kremer, David;Kuery, Patrick
通讯作者：
Kuery, Patrick
影响因子：
4.7
作者：
Brambilla R;Hurtado A;Persaud T;Esham K;Pearse DD;Oudega M;Bethea JR
通讯作者：
Bethea JR
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG