Overexpression of glia maturation factor reinstates susceptibility to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in glia maturation factor deficient mice.
Overexpression of glia maturation factor reinstates susceptibility to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in glia maturation factor deficient mice.
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DOI：
10.1016/j.nbd.2010.08.003
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发表时间：
2010-12
影响因子：
6.1
通讯作者：
Zaheer, Asgar
中科院分区：
文献类型：
--
作者：
Zaheer, Smita;Wu, Yanghong;Sahu, Shailendra K.;Zaheer, Asgar
关键词：
神经胶质成熟因子 (GMF) 是我们实验室发现并表征的一种主要中枢神经系统定位蛋白。我们之前证明，GMF 是脑细胞中促炎细胞因子/趋化因子过度产生和释放的上游调节因子，导致少突胶质细胞、髓磷脂形成细胞和神经元的破坏。我们还报道，缺乏内源性 GMF（GMF 缺陷，GMF-KO）的小鼠对髓磷脂少突胶质细胞糖蛋白肽 35-55（MOG35-55）诱导的 EAE 具有抵抗力，因为免疫仅诱导延迟性 EAE，且严重程度降低。在本研究中，我们表明复制缺陷型腺病毒-GMF构建体引起GMF-KO小鼠的CNS中GMF的表达，并恢复MOG35-55诱导的早期和严重的EAE。我们的结果表明，MOG35-55 免疫仅在缺乏内源性 GMF 的小鼠中引起轻微的 EAE 和炎症/脱髓鞘。 GMF-KO 小鼠中 EAE 发生率的降低与细胞因子/趋化因子表达的显着降低一致。使用腺-GMF-病毒 (Adv-GMF) 载体重新引入 GMF 后，GMF-KO 小鼠中 EAE 的严重程度恢复到完全成熟的水平。与临床发现一致，对患有 EAE 的小鼠的 CNS 进行组织学检查，发现野生型 (Wt)、GMF-KO 和重新引入 GMF 的 GMF-KO 小鼠 (GMF-KO + Adv-GMF) 之间存在显着差异。对患有 EAE 的小鼠的脊髓切片进行了单核细胞浸润（炎症）和髓磷脂损失（脱髓鞘）的分析。在 Wt 小鼠中，在 EAE 高峰期，40% 的脊髓象限脱髓鞘呈阳性，45% 的脊髓象限炎症呈阳性。在 EAE 严重程度减轻的 GMF-KO 小鼠中发现浸润（15%）和脱髓鞘（10%）显着减少。在 GMF-KO 小鼠中重新引入 GMF 后，MOG35-55 免疫引起广泛的单核细胞浸润 (48%) 和脱髓鞘 (46%)，与免疫的 Wt 小鼠中观察到的情况类似。与 EAE 的发病、严重程度峰值和恢复期相对应的三个时间点小鼠脊髓中细胞因子/趋化因子的水平显示，与 GMF-KO 和 GMF-KO + Adv-LacZ 小鼠相比，Wt 和 GMF-KO + Adv-GMF 小鼠中 IFN-γ、TNF-α、GM-CSF 和 MCP-1 显着大幅增加。
Glia maturation factor (GMF), a primarily CNS localized protein was discovered and characterized in our laboratory. We previously demonstrated that GMF is the upstream regulator for excessive production and release of proinflammatory cytokines /chemokines in brain cells leading to the destruction of oligodendrocytes, the myelin forming cells, and neurons. We also reported that mice lacking endogenous GMF (GMF-deficient, GMF-KO) were resistant to myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35-55) induced EAE, since immunization induced only delayed EAE with diminished severity. In the present study we show that a replication-defective adenovirus-GMF construct caused expression of GMF in CNS of GMF-KO mice and reinstated MOG35-55 induced early and severe EAE. Our results show that MOG35-55 immunization caused only a muted EAE and inflammation/demyelination in mice lacking endogenous GMF. The diminished incidence of EAE in GMF-KO mice was consistent with the significantly reduced expressions of cytokines/chemokines. The muted severity of EAE in GMF-KO mice was restored to full blown levels upon reintroduction of GMF using an adeno-GMF-virus (Adv-GMF) vector. Consistent with the clinical findings, histological examination of the CNS of mice with EAE revealed profound differences between wild type (Wt), GMF-KO, and GMF-KO mice with re-introduced GMF (GMF-KO +Adv-GMF). Spinal cord sections from mice with EAE were analyzed for the infiltration of mononuclear cells (inflammation) and myelin loss (demyelination). In Wt mice, 40% of spinal cord quadrants were positive for demyelination and 45% of spinal cord quadrants were positive for inflammation at the peak of EAE. Drastically reduced infiltrates (15%) and demyelination (10%) was found in GMF-KO mice that developed reduced severity of EAE. Upon GMF reintroduction in GMF-KO mice, MOG35-55 immunization caused extensive monocytes infiltration (48%) and demyelination (46%), similar to that observed in the immunized Wt mice. The levels of cytokine/chemokine in the spinal cords of mice at three time points, corresponding to the onset, peak severity and recovery period of EAE, show a distinct pattern of very large increases in IFN-γ, TNF-α, GM-CSF and MCP-1 in Wt and GMF-KO +Adv-GMF mice compared to GMF-KO and GMF-KO +Adv-LacZ mice.
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影响因子：
5.5
作者：
Al-Omaishi, J;Bashir, R;Gendelman, HE
通讯作者：
Gendelman, HE
影响因子：
3.3
作者：
Thangavel, R.;Van Hoesen, G. W.;Zaheer, A.
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影响因子：
4.4
作者：
Zaheer, Asgar;Zaheer, Smita;Lim, Ramon
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Lim, Ramon
影响因子：
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作者：
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Epplen, J. T.
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作者：
Lim, R;Zaheer, A;Oberley, LW
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Oberley, LW