Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu.
Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu.
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DOI：
10.4049/jimmunol.1002218
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发表时间：
2011-01-15
期刊：
影响因子：
--
通讯作者：
Singh RR
中科院分区：
文献类型：
--
作者：
Divekar AA;Dubey S;Gangalum PR;Singh RR
系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病，以自身抗原耐受性丧失和自身反应性T细胞活化为特征。调节性T细胞(Treg)在控制自身反应性T细胞的激活中起着关键作用。在这里，我们使用MRL-Faslpr/LPR(MRL/LPR)和MRL-Fas+/+(MRL+/+)小鼠模型来研究SLE中潜在的Treg缺陷的机制。我们发现，与非自身免疫的C3H小鼠相比，MRL品系的淋巴器官中的CD4+CD25+Foxp3+Treg细胞显著增加，尽管表型发生了变化(CD62L-CD69+)，抑制能力降低。对MRL/LPR小鼠Treg表型改变的机制的搜索导致我们发现MRL/LPR小鼠Treg细胞中Dice的表达显著减少，microRNA(miRNA，miR)谱发生变化。尽管DICER水平降低，但MRL/LPR Treg细胞显示出几个miRNAs的显著过表达，包括let-7a、let-7f、miR-16、miR-23a、miR-23b、miR-27a和miR-155。使用计算方法，我们确定了一种上调的miRNAs，miR-155，它可以靶向CD62L，从而可能在MRL/LPR小鼠中赋予改变的Treg表型。事实上，在其他正常的(C3H)Treg细胞中诱导miR-155的过表达降低了它们的CD62L的表达，这与MRL/LPR小鼠中改变的Treg表型相似。这些数据提示DICER和miR-155在调节Treg细胞表型中起作用。此外，在疾病小鼠中同时出现DICER不足和miR-155过表达，表明在炎症条件下miRNA调节的DICER不依赖的替代机制。
Systemic lupus erythematosus (SLE) is a chroni c autoimmune disease characterized by loss of tolerance to self-antigens and activation of autoreactive T cells. Regulatory T cells (Treg) play a critical role in controlling the activation of autoreactive T cells. Here, we investigated mechanisms of potential Treg defects in SLE using MRL-Faslpr/lpr (MRL/lpr) and MRL-Fas+/+ (MRL+/+) mouse models. We found a significant increase in CD4+CD25+Foxp3+ Treg cells, albeit with an altered phenotype (CD62L–CD69+) and with a reduced suppressive capacity, in the lymphoid organs of MRL strains compared to non-autoimmune C3H mice. A search for mechanisms underlying the altered Treg phenotype in MRL/lpr mice led us to find a profound reduction in Dicer expression and an altered microRNA (miRNA, miR) profile in MRL/lpr Treg cells. Despite having a reduced level of Dicer, MRL/lpr Treg cells exhibited a significant overexpression of several miRNAs including let-7a, let-7f, miR-16, miR-23a, miR-23b, miR-27a and miR-155. Using computational approaches, we identified one of the upregulated miRNAs, miR-155 that can target CD62L and may thus confer the altered Treg phenotype in MRL/lpr mice. In fact, the induced overexpression of miR-155 in otherwise normal (C3H) Treg cells reduced their CD62L expression, which mimics the altered Treg phenotype in MRL/lpr mice. These data suggest a role of Dicer and miR-155 in regulating Treg cell phenotype. Furthermore, simultaneous appearance of Dicer insufficiency and miR-155 overexpression in diseased mice suggests a Dicer-independent alternative mechanism of miRNA regulation under inflammatory conditions.
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DOI：
10.1084/jem.20061692
发表时间：
2006-10-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cobb BS;Hertweck A;Smith J;O'Connor E;Graf D;Cook T;Smale ST;Sakaguchi S;Livesey FJ;Fisher AG;Merkenschlager M
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DOI：
10.1126/science.1190809
发表时间：
2010-06-25
期刊：
Science (New York, N.Y.)
影响因子：
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