Extracellular MicroRNAs Induce Potent Innate Immune Responses via TLR7/MyD88-Dependent Mechanisms.
Extracellular MicroRNAs Induce Potent Innate Immune Responses via TLR7/MyD88-Dependent Mechanisms.
复制标题
DOI：
10.4049/jimmunol.1700730
复制
发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Chao W
中科院分区：
文献类型：
--
作者：
Feng Y;Zou L;Yan D;Chen H;Xu G;Jian W;Cui P;Chao W
组织缺血，如短暂性心肌缺血，导致细胞RNA（包括微小RNA）释放到循环和细胞外空间中，但对细胞外（前）RNA的生物学功能知之甚少。我们最近报道了人类和啮齿动物来源的心脏RNA诱导细胞因子产生和免疫细胞活化。然而，负责促炎作用的前RNA的身份仍不清楚。在目前的研究中，使用miRNA阵列，我们分析了短暂心肌缺血（45分钟）或假手术后4小时的血浆miRNA。在缺血后升高的38种血浆miRNA中，测试了8种在巨噬细胞和心肌细胞中诱导细胞因子应答的能力。我们发现6个miRNA模拟物（-34a、-122、-133a、-142、-146a、-208a）以剂量依赖性方式诱导细胞因子的产生。尿苷→腺苷突变和RNase预处理可减弱miRNAs（-133a，-146a，-208a）的作用。在TLR 7或MyD 88缺陷的细胞中或通过TLR 7拮抗剂消除了miRNA诱导的细胞因子（MIP 2、TNFα、IL-6）的产生，但在TLR 3或Trif缺陷的细胞中保持相同。在体内，腹腔注射miR-133 a或miR-146 a的小鼠具有显著的腹膜中性粒细胞和单核细胞迁移，其在TLR 7-/-小鼠中显著减弱。此外，这六种miRNA的锁核酸（LNA）抗miRNA抑制剂显著减少心脏RNA诱导的细胞因子产生。综上所述，这些数据表明，ex-miRNA模拟物（-34 a、-122、-133 a、-142、-146 a、-208 a）是有效的先天免疫激活剂，并且miRNA最有可能通过TLR 7信号传导诱导细胞因子产生和白细胞迁移。
Tissue ischemia, such as transient myocardial ischemia, leads to release of cellular RNA including microRNA into the circulation and extracellular space, but the biological function of the extracellular (ex-) RNA is poorly understood. We recently reported that cardiac RNA of both human and rodent origins induced cytokine production and immune cell activation. However, the identity of ex-RNA responsible for the pro-inflammatory effect remains unclear. In the current study, using a miRNA array, we profiled the plasma miRNAs four hours after transient myocardial ischemia (45 min) or sham procedure. Among 38 plasma miRNAs that were elevated following ischemia, eight were tested for their ability to induce cytokine response in macrophages and cardiomyocytes. We found that six miRNA mimics (-34a, -122, -133a, -142, -146a, -208a) induced cytokine production in a dose-dependent manner. The effects of miRNAs (-133a, -146a, -208a) were diminished by uridine→adenosine mutation and by RNase pretreatment. The miRNA-induced cytokine (MIP2, TNFα, IL-6) production was abolished in cells deficient of TLR7 or MyD88 or by a TLR7 antagonist, but remained the same in TLR3- or Trif-deficient cells. In vivo, mice i.p. injected with miR-133a or miR-146a had marked peritoneal neutrophil and monocyte migration, which was significantly attenuated in TLR7-/- mice. Moreover, locked nucleic acid (LNA) anti-miRNA inhibitors of these six miRNAs markedly reduced cardiac RNA-induced cytokine production. Taken together, these data demonstrate that ex-miRNA mimics (-34a, -122, -133a, -142, -146a, -208a) are potent innate immune activators and that the miRNAs most likely induce cytokine production and leukocyte migration through TLR7 signaling.
登录
查看更多内容
影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
18.2
作者：
Ellis, Katrina L.;Cameron, Vicky A.;Richards, A. Mark
通讯作者：
Richards, A. Mark
DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Fabbri, Muller;Paone, Alessio;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
DOI：
10.1161/atvbaha.111.226696
发表时间：
2011-11-01
影响因子：
8.7
作者：
Fichtlscherer, Stephan;Zeiher, Andreas M.;Dimmeler, Stefanie
通讯作者：
Dimmeler, Stefanie