Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury.
Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury.
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DOI：
10.1523/jneurosci.0821-11.2011
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发表时间：
2011-06-08
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影响因子：
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通讯作者：
Stenzel-Poore MP
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作者：
Stevens SL;Leung PY;Vartanian KB;Gopalan B;Yang T;Simon RP;Stenzel-Poore MP
缺血耐受可由多种预处理刺激诱导，包括各种toll样受体（TLR）配体。我们之前已经证明，在小鼠短暂性脑缺血之前，全身给予TLR4配体、脂多糖（LPS）或TLR9配体、未甲基化的CpG ODNs，可以有效地保护小鼠免受缺血性损伤。为了阐明预处理的分子机制，我们比较了TLR配体预处理和短暂缺血预处理的脑基因组图谱。我们发现，暴露于TLR配体和短暂缺血诱导了TLR通路介导的脑基因组变化。有趣的是，所有三种预处理刺激都导致对中风损伤的重编程反应，这些反应聚集在一个共有的13个基因子集上，这在没有事先预处理的中风大脑的基因组图谱中并不明显。对这些共享基因的启动子区域的分析显示了干扰素调节因子（IRF）介导转录所需的序列。该IRF基因网络的重要性通过IRF3或IRF7缺失的小鼠进行了测试。我们的数据表明，这两种转录因子都是TLR介导的预处理和神经保护所必需的。这些研究首次发现了由预处理诱导的神经保护的趋同机制，这种机制可能导致tlr介导的中风反应的重编程，并且需要IRF3和IRF7的存在。
Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand, lipopolysaccharide (LPS) or the TLR9 ligand, unmethylated CpG ODNs prior to transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain genomic profiles in response to preconditioning with these TLR ligands and to preconditioning via exposure to brief ischemia. We found that exposure to the TLR ligands and brief ischemia induced genomic changes in the brain characteristic of a TLR pathway mediated response. Interestingly, all three preconditioning stimuli resulted in a reprogrammed response to stroke injury that converged on a shared subset of 13 genes not evident in the genomic profile from brains that were subjected to stroke without prior preconditioning. Analysis of the promoter region of these shared genes showed sequences required for interferon regulatory factor (IRF) mediated transcription. The importance of this IRF gene network was tested using mice deficient in IRF3 or IRF7. Our data show that both transcription factors are required for TLR mediated preconditioning and neuroprotection. These studies are the first to discover a convergent mechanism of neuroprotection induced by preconditioning—one that potentially results in reprogramming of the TLR-mediated response to stroke and requires the presence of IRF3 and IRF7.