Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease
Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease
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DOI：
10.1073/pnas.0905063106
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发表时间：
2009-11-03
影响因子：
11.1
通讯作者：
Foster, Paul S.
中科院分区：
文献类型：
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作者：
Mattes, Joerg;Collison, Adam;Foster, Paul S.
过敏性哮喘是一种肺部炎症性疾病，其特征是T辅助2(T(H)2)淋巴细胞对吸入抗原的异常反应。尽管天然免疫细胞上存在的Toll样受体(TLRs)在感知分子模式和编程适应性T细胞反应中发挥着关键作用，但导致T(H)2反应产生的分子机制尚不清楚。在这里，我们表明，在体内激活TLR4的房间尘螨抗原导致诱导过敏性疾病，这一过程与表达一个独特的子集的小，非编码microRNAs。选择性阻断microRNA(MiR)-126可抑制哮喘表型，导致T(H)2反应减弱、炎症、呼吸道高反应性、嗜酸性粒细胞募集和粘液高分泌。MIR-126阻断导致POU结构域2类结合因子1表达增强，从而激活转录因子PU。1通过负调控GATA3表达改变T(H)2细胞功能。综上所述，这项研究提出了miRNA表达与哮喘发病机制之间的功能联系，我们的数据表明，在呼吸道中靶向miRNA可能会导致过敏性哮喘的抗炎治疗。
Allergic asthma is an inflammatory disease of the lung characterized by abnormal T helper-2 (T(H)2) lymphocyte responses to inhaled antigens. The molecular mechanisms leading to the generation of T(H)2 responses remain unclear, although toll-like receptors (TLRs) present on innate immune cells play a pivotal role in sensing molecular patterns and in programming adaptive T cell responses. Here we show that in vivo activation of TLR4 by house dust mite antigens leads to the induction of allergic disease, a process that is associated with expression of a unique subset of small, noncoding microRNAs. Selective blockade of microRNA (miR)-126 suppressed the asthmatic phenotype, resulting in diminished T(H)2 responses, inflammation, airways hyperresponsiveness, eosinophil recruitment, and mucus hypersecretion. miR-126 blockade resulted in augmented expression of POU domain class 2 associating factor 1, which activates the transcription factor PU. 1 that alters T(H)2 cell function via negative regulation of GATA3 expression. In summary, this study presents a functional connection between miRNA expression and asthma pathogenesis, and our data suggest that targeting miRNA in the airways may lead to anti-inflammatory treatments for allergic asthma.