Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2
Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2
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DOI：
10.2353/ajpath.2006.051113
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发表时间：
2006-06-01
影响因子：
6
通讯作者：
Hubbs, Ann F.
中科院分区：
文献类型：
--
作者：
Ma, Qiang;Battelli, Lori;Hubbs, Ann F.
核因子红细胞2相关因子2（Nrf2）是一种抗氧化剂激活的帽“n”领碱性亮氨酸拉链转录因子。为了评估Nrf2在抗氧化反应中的功能，我们检查了Nrf2基因靶向破坏的小鼠。Nrf2基因敲除小鼠出现了复杂的疾病表现，大多数小鼠表现出狼疮样自身免疫综合征，其特征为多器官炎性病变，女性明显占优势，在年轻成年期出现抗双链DNA抗体，血管内沉积的免疫球蛋白复合物，以及由于快速进展的膜增生性肾小球肾炎导致的过早死亡。机制分析表明，裸小鼠表现出增强的CD4（+）T细胞增殖反应，改变的CD4（+）和CD8（+）细胞的比例，并增加组织中的氧化损伤。抗氧化剂诱导的基因表达的分析表明，敲除小鼠缺乏的基础和诱导表达的某些阶段2解毒酶和抗氧化剂基因在肝脏和淋巴细胞在体内。我们的研究结果表明，Nrf2介导的重要的抗氧化功能参与控制外周淋巴细胞的稳态和自身免疫监视。
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an antioxidant-activated cap "n" collar basic leucine zipper transcription factor. To assess the function of Nrf2 in the antioxidant response, we examined mice with targeted disruption of the Nrf2 gene. Nrf2-null mice developed complex disease manifestations, with a majority exhibiting a lupus-like autoimmune syndrome characterized by multiorgan inflammatory lesions with a marked female predominance, appearance of anti-double-stranded DNA antibodies in young adulthood, intravascular deposition of inummoglobulin complexes in blood vessels, and premature death due to rapidly progressing membranoproliferative glomerular nephritis. Mechanistic analyses revealed that the null mice showed enhanced proliferative response of CD4(+) T cells, altered ratios of CD4(+) and CD8(+) cells, and increased oxidative lesions in tissues. Analyses of antioxidant-induced gene expression showed that the knockout mice were devoid of the basal and inducible expression of certain phase 2 detoxification enzymes and antioxidant genes in hepatic and lymphoid cells in vivo. Our findings suggest that Nrf2 mediates important antioxidant functions involved in the control of peripheral lymphocyte homeostasis and autoimmune surveillance.