The SOD1 transgene expressed in erythroid cells alleviates fatal phenotype in congenic NZB/NZW-F1 mice
The SOD1 transgene expressed in erythroid cells alleviates fatal phenotype in congenic NZB/NZW-F1 mice
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DOI：
10.1080/10715762.2016.1178388
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发表时间：
2016-05
影响因子：
3.3
通讯作者：
Noriyuki Otsuki;Tasuku Konno;Toshihiro Kurahashi;Saori Suzuki;Jaeyong Lee;F. Okada;Y. Iuchi;T. Homma;J. Fujii
中科院分区：
文献类型：
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作者：
Noriyuki Otsuki;Tasuku Konno;Toshihiro Kurahashi;Saori Suzuki;Jaeyong Lee;F. Okada;Y. Iuchi;T. Homma;J. Fujii
超氧化物歧化酶1 （SOD1）缺乏引起的氧化应激可导致C57BL/6小鼠的贫血和自身免疫反应，其表型类似于自身免疫性溶血性贫血（AIHA）和系统性红斑狼疮（SLE），并加重新西兰黑（NZB）小鼠的AIHA发病机制。我们在此报道了活性氧（ROS）在遗传性SLE模型小鼠（即NZB ×新西兰白（NZW）菌株F1小鼠）中的作用。在整个成年期，F1小鼠的红细胞（rbc）中的ROS水平与NZW小鼠相似，但低于NZB小鼠。关于SLE的发病机制，我们通过建立相应的同源F1小鼠，研究了SOD1缺乏或人SOD1在红细胞中过表达的影响。SOD1缺乏导致F1小鼠红细胞中ROS生成、高铁血红蛋白含量和过氧还蛋白高氧化水平升高，这些都与氧化应激升高相一致。然而，虽然红细胞中人类SOD1的过表达延长了基因F1小鼠的寿命，但与野生型F1小鼠相比，SOD1缺乏对寿命没有影响。人们普遍认为，NZW小鼠在免疫系统中具有幼虫缺陷，NZB小鼠在F1小鼠中引发自身免疫反应。我们的研究结果表明，来自NZB小鼠背景的氧化损伤在触发异常免疫反应中具有功能性作用，导致F1小鼠的致命反应。
Abstract Oxidative stress due to a superoxide dismutase 1 (SOD1) deficiency causes anemia and autoimmune responses, which are phenotypically similar to autoimmune hemolytic anemia (AIHA) and systemic lupus erythematosus (SLE) in C57BL/6 mice and aggravates AIHA pathogenesis in New Zealand black (NZB) mice. We report herein on an evaluation of the role of reactive oxygen species (ROS) in a model mouse with inherited SLE, that is, F1 mice of the NZB × New Zealand white (NZW) strain. The ROS levels within red blood cells (RBCs) of the F1 mice were similar to the NZW mice but lower compared to the NZB mice throughout adult period. Regarding SLE pathogenesis, we examined the effects of an SOD1 deficiency or the overexpression of human SOD1 in erythroid cells by establishing corresponding congenic F1 mice. A SOD1 deficiency caused an elevation in ROS production, methemoglobin content, and hyperoxidation of peroxiredoxin in RBC of the F1 mice, which were all consistent with elevated oxidative stress. However, while the overexpression of human SOD1 in erythroid cells extended the life span of the congenic F1 mice, the SOD1 deficiency had no effect on life span compared to wild-type F1 mice. It is generally recognized that NZW mice possess a larval defect in the immune system and that NZB mice trigger an autoimmune reaction in the F1 mice. Our results suggest that the oxidative insult originated from the NZB mouse background has a functional role in triggering an aberrant immune reaction, leading to fatal responses in F1 mice.