Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE.
Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE.
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DOI：
10.1186/s12974-015-0407-4
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发表时间：
2016-01-19
影响因子：
9.3
通讯作者：
Dore-Duffy P
中科院分区：
文献类型：
--
作者：
Esen N;Katyshev V;Serkin Z;Katysheva S;Dore-Duffy P
在大脑中，慢性炎症活动可能导致氧气和葡萄糖的输送受损，这表明旨在恢复代谢平衡的治疗方法可能是有用的。体内暴露于慢性轻度常压缺氧（10%氧气）导致许多内源性适应，包括血管重塑（血管可塑性）。血管可塑性促进组织存活。我们以前已经表明，诱导适应性血管可塑性调节髓鞘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）的疾病模式。在本研究中，我们定义了适应低氧功能改善EAE的体征和症状的机制，并首次表明组织缺氧可能从根本上改变神经退行性疾病。用MOG免疫C57 BL/6小鼠，将其中一些小鼠保持在低氧室中（第0天）并暴露于10%氧气中3周，而另一些保持在常氧环境中。低氧组和常氧组均包括假免疫对照。在临床前和疾病高峰期处死动物，用于组织收集和分析。暴露于轻度缺氧减少炎症的组织学证据。在缺氧脊髓中发现分化簇（CD）4+ T细胞数量减少，与延迟的Th 17特异性细胞因子反应相关。低氧诱导的变化并没有改变外周T细胞对MOG肽的敏感性。暴露于轻度缺氧诱导抗炎性IL-10水平显著增加，脊髓CD 25 + FoxP 3 + T调节细胞数量增加。对轻度缺氧的适应激发了许多内源性适应，从而诱导抗炎环境。对这些机制的深入了解可能会为神经退行性疾病的治疗找到新的靶点。
In the brain, chronic inflammatory activity may lead to compromised delivery of oxygen and glucose suggesting that therapeutic approaches aimed at restoring metabolic balance may be useful. In vivo exposure to chronic mild normobaric hypoxia (10 % oxygen) leads to a number of endogenous adaptations that includes vascular remodeling (angioplasticity). Angioplasticity promotes tissue survival. We have previously shown that induction of adaptive angioplasticity modulates the disease pattern in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). In the present study, we define mechanisms by which adaptation to low oxygen functionally ameliorates the signs and symptoms of EAE and for the first time show that tissue hypoxia may fundamentally alter neurodegenerative disease. C57BL/6 mice were immunized with MOG, and some of them were kept in the hypoxia chambers (day 0) and exposed to 10 % oxygen for 3 weeks, while the others were kept at normoxic environment. Sham-immunized controls were included in both hypoxic and normoxic groups. Animals were sacrificed at pre-clinical and peak disease periods for tissue collection and analysis. Exposure to mild hypoxia decreased histological evidence of inflammation. Decreased numbers of cluster of differentiation (CD)4+ T cells were found in the hypoxic spinal cords associated with a delayed Th17-specific cytokine response. Hypoxia-induced changes did not alter the sensitization of peripheral T cells to the MOG peptide. Exposure to mild hypoxia induced significant increases in anti-inflammatory IL-10 levels and an increase in the number of spinal cord CD25+FoxP3+ T-regulatory cells. Acclimatization to mild hypoxia incites a number of endogenous adaptations that induces an anti-inflammatory milieu. Further understanding of these mechanisms system may pinpoint possible new therapeutic targets to treat neurodegenerative disease.