Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia.
Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia.
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DOI：
10.1002/glia.22680
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发表时间：
2014-08
期刊：
影响因子：
6.2
通讯作者：
Nakabeppu, Yusaku
中科院分区：
文献类型：
--
作者：
Nomaru, Hiroko;Sakumi, Kunihiko;Katogi, Atsuhisa;Ohnishi, Yoshinori N.;Kajitani, Kosuke;Tsuchimoto, Daisuke;Nestler, Eric J.;Nakabeppu, Yusaku
Fosb基因编码激活蛋白-1转录因子复合物的亚基。Fosb mRNA经选择性剪接后形成两个成熟mRNA，即Fosb和ΔFosb，分别编码全长FOSB和ΔFOSB蛋白。Fosb产物在几个大脑区域表达。此外，Fosb基因敲除小鼠表现出抑郁样行为和成年自发性癫痫，在神经和精神疾病中发挥重要作用。Fosb产物的研究几乎完全集中在神经元上;它们在神经胶质细胞中的功能仍有待探索。在这项研究中，我们发现小胶质细胞表达与海马神经元相同水平的Fosb和ΔFosb mRNA，并且使用微阵列分析，我们确定了六个表达依赖于Fosb产物的小胶质细胞基因。在这些基因中，我们集中在C5 ar 1和C5 ar 2，它们编码补体C5 a的受体。在孤立的Fosb无效的小胶质细胞，对截短形式的C5 a的趋化反应显着低于野生型细胞。与野生型小鼠相比，Fosb基因敲除小鼠对红藻氨酸诱导的癫痫发作具有显著的抵抗力。红藻氨酸给药后24小时，野生型海马中C5 ar 1 mRNA水平和C5 aR 1免疫反应性增加;然而，这种诱导在Fosb缺失海马中显著减少。此外，红藻氨酸管理后的小胶质细胞活化显着减少Fosb-空海马，所示的CD 68免疫反应性，形态学变化和IL-6和TNF mRNA的水平降低显着减少，虽然没有变化的Iba-1阳性细胞的数量进行了观察。这些研究结果表明，在兴奋性毒性下，Fosb产品有助于通过调节小胶质细胞C5 ar 1和C5 ar 2的表达在海马神经炎症反应。
The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression.
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影响因子：
4.7
作者：
Ager RR;Fonseca MI;Chu SH;Sanderson SD;Taylor SM;Woodruff TM;Tenner AJ
通讯作者：
Tenner AJ
影响因子：
12.4
作者：
Kurushima, H;Ohno, M;Nakabeppu, Y
通讯作者：
Nakabeppu, Y
DOI：
10.1124/jpet.102.035048
发表时间：
2003-01-01
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
Nakabeppu, Y