The Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
PLoS One. 2011;6(11):e27580. doi: 10.1371/journal.pone.0027580. Epub 2011 Nov 16.
Physiological stress evokes rapid changes in both the innate and adaptive immune response. Immature αβ T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs are a class of small, non-coding RNAs that regulate global gene expression by targeting diverse mRNAs for degradation. We hypothesized that a subset of thymically encoded microRNAs would be stress responsive and modulate thymopoiesis. We performed microRNA profiling of thymic microRNAs isolated from control or stressed thymic tissue obtained from mice. We identified 18 microRNAs that are dysregulated >1.5-fold in response to lipopolysaccharide or the synthetic corticosteroid dexamethasone. These included the miR-17-90 cluster, which have anti-apoptotic functions, and the miR-181 family, which contribute to T cell tolerance. The stress-induced changes in the thymic microRNAs are dynamically and distinctly regulated in the CD4(-)CD8(-), CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) thymocyte subsets. Several of the differentially regulated murine thymic miRs are also stress responsive in the heart, kidney, liver, brain, and/or spleen. The most dramatic thymic microRNA down modulated is miR-181d, exhibiting a 15-fold reduction following stress. This miR has both similar and distinct gene targets as miR-181a, another member of miR-181 family. Many of the differentially regulated microRNAs have known functions in thymopoiesis, indicating that their dysregulation will alter T cell repertoire selection and the formation of naïve T cells. This data has implications for clinical treatments involving anti-inflammatory steroids, ablation therapies, and provides mechanistic insights into the consequences of infections.
生理应激会迅速改变固有免疫和适应性免疫反应。在胸腺中发育的未成熟的αβ T 细胞对应激特别敏感，感染和/或暴露于脂多糖或糖皮质激素会引发快速凋亡程序。microRNAs 是一类小的非编码 RNA，通过靶向不同的 mRNA 进行降解来调节全局基因表达。我们假设一部分胸腺编码的 microRNAs 会对压力做出反应并调节胸腺生成。我们对从对照或应激胸腺组织中分离的胸腺 microRNAs 进行了 microRNA 谱分析。我们鉴定了 18 个 microRNAs，它们对脂多糖或合成皮质类固醇地塞米松的反应超过 1.5 倍。其中包括具有抗凋亡功能的 miR-17-90 簇，以及有助于 T 细胞耐受的 miR-181 家族。应激诱导的胸腺 microRNAs 的变化在 CD4(-)CD8(-)、CD4(+)CD8(+)、CD4(+)CD8(-)和 CD4(-)CD8(+)胸腺细胞亚群中是动态和明显调节的。几种差异调节的鼠胸腺 miRs 在心脏、肾脏、肝脏、大脑和/或脾脏中也对压力有反应。下调最明显的胸腺 microRNA 是 miR-181d，应激后其表达降低了 15 倍。该 miR 与 miR-181a（miR-181 家族的另一个成员）具有相似和不同的基因靶标。许多差异调节的 microRNAs 在胸腺生成中有已知的功能，这表明它们的失调将改变 T 细胞库选择和形成幼稚 T 细胞。该数据对涉及抗炎类固醇、消融疗法的临床治疗具有重要意义，并为感染的后果提供了机制上的见解。
