Transgenic expression of microRNA-181d augments the stress-sensitivity of CD4(+)CD8(+) thymocytes.
Transgenic expression of microRNA-181d augments the stress-sensitivity of CD4(+)CD8(+) thymocytes.
复制标题
DOI：
10.1371/journal.pone.0085274
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
van Oers NS
中科院分区：
文献类型：
--
作者：
Belkaya S;van Oers NS
感染、创伤、手术、酗酒、营养不良和/或怀孕引起的生理应激会导致未成熟的 CD4+CD8+ 胸腺细胞大量消耗。我们之前在脂多糖 (LPS) 或合成糖皮质激素地塞米松 (Dex) 诱导的全身应激下，在胸腺中鉴定了 18 种不同的应激反应性 microRNA (miR)。 MiR 是短的非编码 RNA，通过靶向不同的 mRNA 在免疫系统中发挥关键作用，这表明它们在胸腺中响应压力的调节可能会影响胸腺生成。 MiR-181d 就是一种这样的应激反应性 miR，表现出 15 倍的表达下调。我们利用转基因和基因靶向方法来研究 miR-181d 在正常和应激条件下对胸腺生成的影响。发育中胸腺细胞中 miR-181d 的过度表达减少了未成熟 CD4+CD8+ 胸腺细胞的总数。与野生型对照相比，LPS 或 Dex 注射导致这些细胞的损失增加 4 倍。开发出一种基因敲除小鼠来选择性消除 miR-181d，从而使间隔紧密且连续的家族成员 miR-181c 保持完整。仅靶向消除 miR-181d 会导致与野生型小鼠相似的胸腺应激反应。这些实验表明其他三个 miR-181 家族成员中的一个或多个具有重叠或补偿功能。野生型与转基因小鼠胸腺细胞的基因表达比较表明，miR-181d 针对许多应激、代谢和信号传导途径。这些发现表明，选定的 miR 可增强体内应激介导的胸腺复旧。
Physiological stress resulting from infections, trauma, surgery, alcoholism, malnutrition, and/or pregnancy results in a substantial depletion of immature CD4+CD8+ thymocytes. We previously identified 18 distinct stress-responsive microRNAs (miRs) in the thymus upon systemic stress induced by lipopolysaccharide (LPS) or the synthetic glucocorticoid, dexamethasone (Dex). MiRs are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs, suggesting that their modulation in the thymus in response to stress could impact thymopoiesis. MiR-181d is one such stress-responsive miR, exhibiting a 15-fold down-regulation in expression. We utilized both transgenic and gene-targeting approaches to study the impact of miR-181d on thymopoiesis under normal and stress conditions. The over-expression of miR-181d in developing thymocytes reduced the total number of immature CD4+CD8+ thymocytes. LPS or Dex injections caused a 4-fold greater loss of these cells when compared with the wild type controls. A knockout mouse was developed to selectively eliminate miR-181d, leaving the closely spaced and contiguous family member miR-181c intact. The targeted elimination of just miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice. These experiments suggest that one or more of three other miR-181 family members have overlapping or compensatory functions. Gene expression comparisons of thymocytes from the wild type versus transgenic mice indicated that miR-181d targets a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo.
登录
查看更多内容
DOI：
10.1016/j.clim.2013.01.011
发表时间：
2013-04
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
de la Morena MT;Eitson JL;Dozmorov IM;Belkaya S;Hoover AR;Anguiano E;Pascual MV;van Oers NSC
通讯作者：
van Oers NSC
影响因子：
20.3
作者：
Heinonen, Krista M.;Vanegas, Juan Ruiz;Perreault, Claude
通讯作者：
Perreault, Claude
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.8
作者：
Belkaya, Serkan;Murray, Sean E.;van Oers, Nicolai S. C.
通讯作者：
van Oers, Nicolai S. C.
DOI：
10.4049/jimmunol.1103175
发表时间：
2012-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kirigin FF;Lindstedt K;Sellars M;Ciofani M;Low SL;Jones L;Bell F;Pauli F;Bonneau R;Myers RM;Littman DR;Chong MM
通讯作者：
Chong MM