Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia
Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia
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DOI：
10.1073/pnas.0403620101
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发表时间：
2004-06-29
影响因子：
11.1
通讯作者：
Johnson, JA
中科院分区：
文献类型：
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作者：
Lee, JM;Chan, KM;Johnson, JA
NF-E2 相关因子 2 (Nrf2) 是一种碱性亮氨酸拉链转录因子，通过介导抗氧化反应元件驱动的解毒和抗氧化基因的协调上调，在细胞防御机制中发挥着关键作用。在这里，我们报告说，由于受损红细胞的隔离增加，Nrf2 的靶向破坏会导致再生免疫介导的溶血性贫血。 Nrf2(-/-)小鼠的脾肿大和脾毒性增加了Nrf2(-/-)小鼠发生溶血性贫血和脾髓外造血的可能性。为了支持这一点，血液学分析显示 Nrf2(-/-) 小鼠患有贫血并伴有红细胞形态异常（即豪威尔-乔利小体、棘红细胞和裂红细胞）。此外，Nrf2(-/-)红细胞对H2O2诱导的溶血更加敏感，与Nrf2(+/+)小鼠相比，Nrf2(-/-)小鼠红细胞结合的IgG水平显着升高。由于 IgG 在红细胞存在氧化损伤的情况下与红细胞结合（无论 Nrf2 基因型如何），因此这些数据支持 Nrf2(-/-) 红细胞与 Nrf2(+/+) 细胞相比具有更高水平的损伤。最后，体内注射H2O2后，与Nrf2(+/+)小鼠相比，Nrf2(-/-)小鼠表现出红细胞结合IgG水平增加，这表明谷胱甘肽减少和H2O2增加使Nrf2(-/-)小鼠更容易受到毒性影响。综上所述，这些观察结果表明，由于抗氧化能力下降而导致的氧化应激的慢性增加会使红细胞变得敏感，并导致 Nrf2(-/-) 小鼠溶血性贫血，这表明 Nrf2-抗氧化反应元件途径在细胞抗氧化防御系统中发挥着关键作用。
A basic leucine zipper transcription factor, NF-E2-related factor 2 (Nrf2), plays a critical role in the cellular defense mechanism by mediating a coordinate up-regulation of antioxidant responsive element-driven detoxification and antioxidant genes. Here, we report that targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia due to increased sequestration of damaged erythrocytes. Splenomegaly and spleen toxicity in Nrf2(-/-) mice raised a possibility of hemolytic anemia and splenic extramedullary hematopoiesis in Nrf2(-/-) mice. In support of this, hematology analysis revealed that Nrf2(-/-) mice suffer from anemia with abnormal red cell morphologies (i.e., Howell-Jolly bodies, acantocytes, and schistocytes). In addition, Nrf2(-/-) erythrocytes were more sensitive to H2O2-induced hemolysis, and erythrocyte-bound IgG levels were markedly increased in Nrf2(-/-) mice compared with Nrf2(+/+) mice. Because IgG bound to erythrocytes in the presence of oxidative damage in erythrocytes (regardless of Nrf2 genotype), these data support that Nrf2(-/-) erythrocytes have higher levels of damage compared with Nrf2(+/+) cells. Finally, Nrf2(-/-) mice showed increased levels of erythrocyte-bound IgG compared with Nrf2(+/+) mice after H2O2 injection in vivo, suggesting that the decreased glutathione and increased H2O2 render the Nrf2(-/-) mice more susceptible to toxicity. Taken together, these observations indicate that a chronic increase in oxidative stress due to decreased antioxidant capacity sensitizes erythrocytes and causes hemolytic anemia in Nrf2(-/-) mice, suggesting a pivotal role of Nrf2- antioxidant responsive element pathway in the cellular antioxidant defense system.