The Absence of the Pro-antioxidant Transcription Factor Nrf2 Exacerbates Experimental Autoimmune Encephalomyelitis
The Absence of the Pro-antioxidant Transcription Factor Nrf2 Exacerbates Experimental Autoimmune Encephalomyelitis
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DOI：
10.1093/toxsci/kfp274
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Johnson, Jeffrey A.
中科院分区：
文献类型：
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作者：
Johnson, Delinda A.;Amirahmadi, Sara;Johnson, Jeffrey A.
多发性硬化症（MS）是一种自身免疫性疾病，其特征是CD4(+) T细胞外周活化，迁移到中枢神经系统（CNS），并对髓磷脂和少突胶质细胞发动自身免疫性神经炎症攻击。继发于这些事件的，是由持续激活的小胶质细胞和星形胶质细胞产生的炎症介导的活性氧和活性氮，然而同样具有破坏性。核因子-红细胞2相关因子2 （Nuclear factor-erythroid 2 related factor 2, Nrf2）是一种基本的亮氨酸拉链转录因子，调控多种保护性抗氧化和解毒酶的基因表达。在这里，我们描述了Nrf2在MS的急性自身免疫性模型，实验性自身免疫性脑脊髓炎（EAE）中对先天和适应性免疫反应的调节。野生型（WT）小鼠和Nrf2敲除小鼠用髓鞘少突胶质细胞糖蛋白（MOG 35-55）免疫，每天监测疾病的临床评分。Nrf2的破坏导致了更严重的临床病程，更快速的发病，以及更大比例的小鼠患病。此外，观察到脊柱免疫细胞浸润和神经胶质细胞活化增加。同时，我们观察到与WT小鼠相比，Nrf2缺陷小鼠中炎症酶（iNOS, phox-47， gp9I-phox和phox-67），细胞因子（ifn - γ, il -1 -b， tnf - α和IL-12）和趋化因子（BLC和MIG）基因表达水平升高，支持Nrf2可以调节自身免疫神经炎症反应的观点。我们的研究结果表明，Nrf2的缺失加剧了EAE的发展，因此表明Nrf2的激活可能会减弱自身免疫性疾病（如MS）以及其他伴有神经炎症的神经退行性疾病的发病机制。
Multiple sclerosis (MS) is an autoimmune disease characterized by peripheral activation of CD4(+) T cells that migrate into the central nervous system (CNS) and mount an autoimmune neuroinflammatory attack on myelin and oligodendrocytes. Secondary to these events, however equally destructive, is the generation of inflammatory-mediated reactive oxygen and nitrogen species generated by persistently activated microglia and astrocytes. Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a basic leucine zipper transcription factor that regulates genetic expression of many protective antioxidant and detoxication enzymes. Here we describe the Nrf2 modulation of innate and adaptive immune responses in an acute autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE). Wild-type (WT) mice and Nrf2 knockout mice were immunized with myelin oligodenclrocyte glycoprotein (MOG 35-55) and monitored daily for clinical scores of disease. Disruption of Nrf2 resulted in a more severe clinical course, a more rapid onset, and a greater percentage of mice with the disease. Furthermore, increased immune cell infiltration and glial cell activation in spine was observed. In conjunction, we observed increased inflammatory enzyme (iNOS, phox-47, gp9I-phox, and phox-67), cytokine (IFN-gamma, IL1-b, TNF-alpha, and IL-12), and chemokine (BLC and MIG) gene expression levels in the Nrf2-deficient mice compared to the WT mice, supporting the notion that Nrf2 can modulate an autoimmune neuroinflammatory response. Our results show that the absence of Nrf2 exacerbates the development of EAE and thus suggests that activation of Nrf2 may then attenuate pathogenesis of autoimmune diseases such as MS as well as other neurodegenerative diseases that present with neuroinflammation.