Toll-like receptor 7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism.
Toll-like receptor 7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism.
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DOI：
10.1161/strokeaha.111.641522
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发表时间：
2012-05
期刊：
影响因子：
8.3
通讯作者：
Stenzel-Poore MP
中科院分区：
文献类型：
--
作者：
Leung PY;Stevens SL;Packard AE;Lessov NS;Yang T;Conrad VK;van den Dungen NN;Simon RP;Stenzel-Poore MP
在脑缺血之前全身施用Toll样受体4（TLR 4）和TLR 9激动剂已显示通过重编程脑对中风的反应来减少缺血性损伤。我们的目标是通过确定TLR 7激动剂是否也能防止中风损伤来探索TLR诱导的神经保护机制。在大脑中动脉闭塞（MCAO）前72小时，对C57 Bl/6、TNF-/-、干扰素调节因子（IRF）7-/-或I型干扰素受体（IFNAR）-/-小鼠皮下施用TLR 7激动剂Gardiquimod（GDQ）。再灌注后测定脑体积和功能结果。测量血浆细胞因子应答和脑中IFN相关基因的mRNA诱导。在MCAO之前，IFNAR-/-小鼠也用TLR 4激动剂（脂多糖）或TLR 9激动剂（CpG）处理，并测量梗死体积。结果表明，GDQ减少了小鼠的梗死体积以及功能缺陷。GDQ预处理在TNF-/-小鼠中提供了强大的神经保护作用，表明TNF不是必需的。GDQ诱导血浆IFNα水平显著增加，IRF 7 −/−和IFNAR−/−小鼠均未受到保护，这表明IFN信号在TLR 7介导的保护中发挥作用。我们的研究提供了第一个证据表明TLR 7预处理可以介导对缺血损伤的神经保护作用。此外，我们表明，保护机制是独特的，从其他TLR预处理配体，它是独立的TNF和IFNAR依赖。
Systemic administration of Toll-like receptor 4 (TLR4) and TLR9 agonists prior to cerebral ischemia, have been shown to reduce ischemic injury by reprogramming the brain’s response to stroke. Our goal was to explore the mechanism of TLR induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury. C57Bl/6, TNF−/−, interferon regulatory factor (IRF)7−/−, or type I interferon receptor (IFNAR)−/− mice were subcutaneously administered the TLR7 agonist Gardiquimod (GDQ) 72 hr prior to middle cerebral artery occlusion (MCAO). Infarct volume and functional outcome were determined following reperfusion. Plasma cytokine responses and induction of mRNA for IFN related genes in the brain were measured. IFNAR−/− mice were also treated with the TLR4 agonist (lipopolysaccharide) or the TLR9 agonist (CpG) prior to MCAO and infarct volumes measured. The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF−/− mice indicating that TNF was not essential. GDQ induced a significant increase in plasma IFNα levels and both IRF7−/− and IFNAR−/− mice failed to be protected, implicating a role for IFN signaling in TLR7 mediated protection. Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.