Reprogramming the response to stroke by preconditioning.
Reprogramming the response to stroke by preconditioning.
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DOI：
10.1161/strokeaha.114.002879
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发表时间：
2014-08
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：
Stevens SL;Vartanian KB;Stenzel-Poore MP
2528卒中2014年8月CpG通过鼻腔给药途径进行预适应，可绕过全身肿瘤坏死因子的诱导，这可诱导脑内肿瘤坏死因子mRNA，并导致脑梗塞面积显著缩小，卒中前血浆中未检测到肿瘤坏死因子。22脑部肿瘤坏死因子的重要性得到了使用脑部直接注射肿瘤坏死因子的研究的支持，在这些研究中，Nawashiro等人23表明，在脑缺血前48小时脑池内注射肿瘤坏死因子显著减少了损伤。相反，全身应用肿瘤坏死因子并不能减少损伤面积。因此，中枢神经系统的低水平炎症反应可能是预适应启动阶段的关键。使用TLR配体的全身预适应在体循环和脑实质中都能诱导明确的反应；然而，TLR刺激的关键作用部位并不是很明显。在一项使用缺乏TLR9的TLR9基因缺失的骨髓嵌合小鼠的研究中强调了系统和大脑反应对TLR预适应诱导的神经保护的潜在贡献，该嵌合小鼠的造血细胞(白细胞)或非造血细胞来源的抗辐射细胞(即内皮细胞、神经元、星形胶质细胞和小胶质细胞)上的TLR9缺失。使用TLR9配体CpG的系统预适应在任何一种嵌合菌株中都无法预防脑缺血。这表明TLR信号在体循环和中枢神经系统中都是必需的，以诱导神经保护。22
2528 Stroke August 2014 the systemic induction of TNF can be bypassed by preconditioning with CpG using an intranasal route of administration, which induced cerebral TNF mRNA and caused a robust reduction in infarct size with no detectable TNF in plasma before stroke. 22 The importance of cerebral TNF is supported by studies using direct TNF administration into the brain, whereby Nawashiro et al23 showed that intracisternal administration of TNF 48 hours before cerebral ischemia significantly reduced injury. In contrast, systemic administration of TNF failed to reduce the injury size. Thus, a low-level inflammatory response in the central nervous system may be critical to the priming phase of preconditioning. Systemic preconditioning with a TLR ligand induces clear responses in both the systemic circulation and the brain parenchyma; however, the critical site-of-action of TLR stimulation is not readily apparent. The potential contribution of both the systemic and brain responses to TLR preconditioning-induced neuroprotection was highlighted in a study using TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells (leukocytes) or radiation-resistant cells of nonhematopoietic origin (ie, endothelial cells, neurons, astrocytes, and microglia). Systemic preconditioning with the TLR9 ligand, CpG, failed to protect against cerebral ischemia in either chimeric strain. This indicates that TLR signaling is required in both the systemic circulation and the central nervous system to induce neuroprotection. 22