Akt3-Mediated Protection Against Inflammatory Demyelinating Disease
Akt3-Mediated Protection Against Inflammatory Demyelinating Disease
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DOI：
10.3389/fimmu.2019.01738
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发表时间：
2019-07-25
影响因子：
7.3
通讯作者：
Shafit-Zagardo, Bridget
中科院分区：
文献类型：
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作者：
DuBois, Juwen C.;Ray, Alex K.;Shafit-Zagardo, Bridget
Akt 是一种丝氨酸/苏氨酸蛋白激酶，在调节多种细胞过程中发挥着重要作用。虽然同工型 Akt1 和 Akt2 分别参与细胞凋亡和胰岛素信号传导，但 Akt3 的作用仍不确定。 Akt3 主要在大脑中表达，小鼠中 Akt3 的完全缺失会导致大脑尺寸减小和损伤后的神经退行性变。此前，我们发现Akt3(-/-)小鼠在髓磷脂少突胶质细胞糖蛋白(MOG)诱导的实验性自身免疫性脑脊髓炎(EAE)动物模型中具有明显更差的临床病程，在该动物模型中，自身反应性免疫细胞进入中枢神经系统，导致炎症、脱髓鞘和轴突损伤。与 WT 相比，Akt3(-/-) 小鼠的脊髓严重脱髓鞘，炎症增加，表明 Akt3 在 EAE 期间具有神经保护作用。为了具体阐述 Akt3 在神经炎症和维持神经元完整性中的作用，我们使用了几种对 Akt3 进行不同操作的小鼠品系。在 EAE 期间，与 WT 小鼠相比，Akt3(Nmf350) 小鼠（Akt3 激酶活性增强）临床评分较低，疾病发作滞后，炎症细胞流入 CNS 延迟，轴突损伤较少。相对于 WT，在 Akt3(Nmf350) 小鼠中还观察到向表达 FOXP3 的 iTreg 的分化效率显着增加。 CD4+T细胞中Akt3条件性缺失的小鼠出现EAE症状较早，脊髓和大脑炎症增加，并且FOXP3+细胞和FOXP3 mRNA表达较少。当神经元中 Akt3 表达被删除 (Syn1-CKO) 时，EAE 结果没有观察到差异。这些结果表明，T 细胞而非神经元中的 Akt3 信号传导对于在炎症性脱髓鞘疾病期间维持 CNS 完整性是必需的。
Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis and insulin signaling, respectively, the role for Akt3 remains uncertain. Akt3 is predominantly expressed in the brain, and total deletion of Akt3 in mice results in a reduction in brain size and neurodegeneration following injury. Previously, we found that Akt3(-/-) mice have a significantly worse clinical course during myelin-oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model in which autoreactive immune cells enter the CNS, resulting in inflammation, demyelination, and axonal injury. Spinal cords of Akt3(-/-) mice are severely demyelinated and have increased inflammation compared to WT, suggesting a neuroprotective role for Akt3 during EAE. To specifically address the role of Akt3 in neuroinflammation and maintaining neuronal integrity, we used several mouse strains with different manipulations to Akt3. During EAE, Akt3(Nmf350) mice (with enhanced Akt3 kinase activity) had lower clinical scores, a lag in disease onset, a delay in the influx of inflammatory cells into the CNS, and less axonal damage compared to WT mice. A significant increased efficiency of differentiation toward FOXP3 expressing iTregs was also observed in Akt3(Nmf350) mice relative to WT. Mice with a conditional deletion of Akt3 in CD4(+) T-cells had an earlier onset of EAE symptoms, increased inflammation in the spinal cord and brain, and had fewer FOXP3(+) cells and FOXP3 mRNA expression. No difference in EAE outcome was observed when Akt3 expression was deleted in neurons (Syn1-CKO). These results indicate that Akt3 signaling in T-cells and not neurons is necessary for maintaining CNS integrity during an inflammatory demyelinating disease.