Rig-I-/- mice develop colitis associated with downregulation of Gαi2
Rig-I-/- mice develop colitis associated with downregulation of Gαi2
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DOI：
10.1038/cr.2007.81
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发表时间：
2007-10-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Zhu-Gang
中科院分区：
文献类型：
--
作者：
Wang, Yi;Zhang, Hong-Xin;Wang, Zhu-Gang
RIG-I（维甲酸诱导基因-I）是一种假定的RNA解旋酶，具有胞质半胱天冬酶募集结构域（CARD），被鉴定为通过诱导I型干扰素产生介导抗病毒免疫的模式识别受体（PRR）。为了进一步研究RIG-1的生物学功能，我们通过同源重组产生Rig-I-/-小鼠，采用与先前报道的策略不同的策略。我们的Rig-I-/-小鼠是可行的和可繁殖的。组织学分析表明，Rig-I-/-小鼠出现结肠炎样表型，并且对硫酸葡聚糖钠诱导的结肠炎的易感性增加。因此，突变小鼠派伊尔集合淋巴结的大小和数量显著减少。突变小鼠外周T细胞亚群的特征是效应T细胞增加，初始T细胞减少，这表明Rig-I在调节T细胞活化方面发挥重要作用。进一步发现Rig-I缺乏导致包括T和B淋巴细胞在内的各种组织中G蛋白α i2亚基（G α i2）的下调。相比之下，用ATRA处理的NB 4细胞中Rig-I的上调伴随着升高的G α 12表达。此外，在共转染的NIH 3 T3细胞中，G α i2启动子活性以Rig-I剂量依赖性方式增加。所有这些发现表明Rig-I在G α i2表达和T细胞活化的调节中具有关键作用。结肠炎的发展可能至少部分与G α 12的下调和T细胞稳态紊乱有关。
RIG-I (retinoid acid-inducible gene-I), a putative RNA helicase with a cytoplasmic caspase-recruitment domain (CARD), was identified as a pattern-recognition receptor (PRR) that mediates antiviral immunity by inducing type I interferon production. To further study the biological function of RIG-1, we generated Rig-I-/- mice through homologous recombination, taking a different strategy to the previously reported strategy. Our Rig-I-/- mice are viable and fertile. Histological analysis shows that Rig-I-/- mice develop a colitis-like phenotype and increased susceptibility to dextran sulfate sodium-induced colitis. Accordingly, the size and number of Peyer's patches dramatically decreased in mutant mice. The peripheral T-cell subsets in mutant mice are characterized by an increase in effector T cells and a decrease in naive T cells, indicating an important role for Rig-I in the regulation of T-cell activation. It was further found that Rig-I deficiency leads to the downregulation of G protein (alpha i2 subunit (G alpha i2) in various tissues, including T and B lymphocytes. By contrast, upregulation of Rig-I in NB4 cells that are treated with ATRA is accompanied by elevated G alpha i2 expression. Moreover, G alpha i2 promoter activity is increased in co-transfected NIH3T3 cells in a Rig-I dose-dependent manner. All these findings suggest that Rig-I has crucial roles in the regulation of G alpha i2 expression and T-cell activation. The development of colitis may be, at least in part, associated with downregulation of G alpha i2 and disturbed T-cell homeostasis.