Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning
Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning
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DOI：
10.1111/j.1471-4159.2009.05972.x
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发表时间：
2009-04-01
影响因子：
4.7
通讯作者：
Lizasoain, Ignacio
中科院分区：
文献类型：
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作者：
Pradillo, Jesus M.;Fernandez-Lopez, David;Lizasoain, Ignacio
已经证明，短暂的缺血事件（缺血预适应，IPC）会导致随后对严重缺血的抵抗（缺血耐受，IT）。我们最近证明了先天免疫，特别是 Toll 样受体 (TLR) 4 在脑缺血中的作用。多项证据表明 TLR4 也可能与 IT 相关。因此，我们现在使用IPC的体内模型来研究TLR4是否参与IT。 6 分钟临时双侧颈总动脉闭塞用于局灶性 IPC，并在 TLR4 缺陷小鼠 (C57BL/10ScNJ) 和正常表达 TLR4 的动物 (C57BL/10ScSn) 上进行。为了评估IPC诱导IT的能力，在IPC后48小时进行永久性大脑中动脉闭塞。通过测定梗塞体积和评估神经学评分来评估中风结果。 IPC 具有神经保护作用，正常表达 TLR4 的小鼠梗塞体积减少，结果更好。与野生型动物相比，TLR4 缺陷小鼠表现出较少的 IPC 诱导的神经保护作用。肿瘤坏死因子α (TNF-α)、诱导型一氧化氮合酶 (iNOS) 和环氧合酶-2 (COX-2) 的蛋白质印迹分析显示，IPC 后 18、24 和 48 小时测量的两个小鼠亚系中这些蛋白的表达均上调，其中在 TLR4 小鼠中更高。同样，在 IPC 后 18、24 和 48 小时观察到核因子 kappa B (NF-kappa B) 激活，在表达 TLR4 的小鼠中更为强烈。这些数据表明 TLR4 信号传导参与大脑耐受性，如 ScSn 和 ScNJ 之间 IPC 产生的神经保护百分比差异所示（60% 与 18%）。在表达 TLR4 的小鼠中，TNF-α、iNOS 和环加氧酶 2 的较高表达以及 NF-κ B 激活可能参与了这种内源性神经保护作用。
It has been demonstrated that a short ischemic event (ischemic preconditioning, IPC) results in a subsequent resistance to severe ischemia (ischemic tolerance, IT). We have recently demonstrated the role of innate immunity and in particular of toll-like receptor (TLR) 4 in brain ischemia. Several evidences suggest that TLR4 might also be involved in IT. Therefore, we have now used an in vivo model of IPC to investigate whether TLR4 is involved in IT. A 6-min temporary bilateral common carotid arteries occlusion was used for focal IPC and it was performed on TLR4-deficient mice (C57BL/10ScNJ) and animals that express TLR4 normally (C57BL/10ScSn). To assess the ability of IPC to induce IT, permanent middle cerebral artery occlusion was performed 48 h after IPC. Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. IPC caused neuroprotection as shown by a reduction in infarct volume and better outcome in mice expressing TLR4 normally. TLR4-deficient mice showed less IPC-induced neuroprotection than wild-type animals. Western blot analysis of tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) showed an up-regulation in the expression of these proteins in both substrains of mice measured 18, 24 and 48 h after IPC, being higher in mice with TLR4. Similarly, nuclear factor-kappa B (NF-kappa B) activation was observed 18, 24 and 48 h after IPC, being more intense in TLR4-expressing mice. These data demonstrate that TLR4 signalling is involved in brain tolerance as shown by the difference in the percentage of neuroprotection produced by IPC between ScSn and ScNJ (60% vs. 18%). The higher expression of TNF-alpha, iNOS and cyclooxygenase-2 and NF-kappa B activation in mice expressing TLR4 is likely to participate in this endogenous neuroprotective effect.