Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation.
Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation.
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DOI：
10.4049/jimmunol.0802954
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发表时间：
2009-03-01
期刊：
影响因子：
--
通讯作者：
Bethea JR
中科院分区：
文献类型：
--
作者：
Brambilla R;Persaud T;Hu X;Karmally S;Shestopalov VI;Dvoriantchikova G;Ivanov D;Nathanson L;Barnum SR;Bethea JR
在CNS中，转录因子NF-κB是炎症和继发性损伤过程的关键调节因子。创伤或疾病后，NF-κ B依赖性基因的表达被激活，导致保护和有害作用。在这项研究中，我们表明，转基因失活的星形胶质细胞NF-κB（胶质细胞酸性蛋白-I κBα显性阴性小鼠）导致降低疾病的严重程度和改善功能恢复后，实验性自身免疫性脑脊髓炎。在疾病的慢性阶段，与野生型相比，转基因小鼠表现出脊髓和脑中白细胞的总体较高的存在，以及CD 8 + CD 122+调节性T细胞的显著较高的百分比，这与临床恢复的时间相关。我们还观察到，脊髓和小脑中促炎基因的表达延迟和减少，而突触传递所必需的神经元特异性分子的损失与野生型小鼠相比是有限的。此外，受影响视网膜中视网膜神经节细胞的死亡几乎被消除，表明神经保护机制的激活。我们的数据表明，抑制星形胶质细胞中的NF-κB导致实验性自身免疫性脑脊髓炎后的神经保护作用，直接涉及星形胶质细胞在这种疾病的病理生理学。
In the CNS, the transcription factor NF-κB is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-κB-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-κB (glial fibrillary acidic protein-IκBα-dominant-negative mice) resulted in reduced disease severity and improved functional recovery following experimental autoimmune encephalomyelitis. At the chronic stage of the disease, transgenic mice exhibited an overall higher presence of leukocytes in spinal cord and brain, and a markedly higher percentage of CD8+CD122+ T regulatory cells compared with wild type, which correlated with the timing of clinical recovery. We also observed that expression of proinflammatory genes in both spinal cord and cerebellum was delayed and reduced, whereas the loss of neuronal-specific molecules essential for synaptic transmission was limited compared with wild-type mice. Furthermore, death of retinal ganglion cells in affected retinas was almost abolished, suggesting the activation of neuro-protective mechanisms. Our data indicate that inhibiting NF-κB in astrocytes results in neuroprotective effects following experimental autoimmune encephalomyelitis, directly implicating astrocytes in the pathophysiology of this disease.
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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：
4.8
作者：
Bjartmar, C;Trapp, BD
通讯作者：
Trapp, BD
影响因子：
3.3
作者：
Calderon, Tina M.;Eugenin, Eliseo A.;Berman, Joan W.
通讯作者：
Berman, Joan W.
影响因子：
4.8
作者：
Aggarwal, S;Ghilardi, N;Gurney, AL
通讯作者：
Gurney, AL
影响因子：
4.4
作者：
Endharti, AT;Rifa'I, M;Suzuki, H
通讯作者：
Suzuki, H