Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway
Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway
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创伤后焦虑与先天免疫受体 TLR9 未能逃避促炎 NFκB 通路有关
DOI：
10.1038/tp.2012.4
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发表时间：
2012
影响因子：
6.8
通讯作者：
Friedman
中科院分区：
文献类型：
--
作者：
Zimmermann;Shaltiel;Barbash;Shenhar-Tsarfaty;Shalev;Berliner;Shelef;Shoham;Friedman
创伤后焦虑主要涉及炎症，但其原因和功能意义尚不清楚。在这里，我们报告说，先天免疫系统Toll样受体9（TLR 9）限制炎症的失败是因果关系与焦虑相关的炎症和TLR 9的特定寡核苷酸激活剂的外周给药可能会防止创伤后应激小鼠的后果。提示NFκ B介导的炎症反应增强参与创伤后表型，我们发现创伤后应激障碍患者血清白细胞介素-1 β升高与症状严重程度和脑体积变化相关。在捕食者气味应激的小鼠中，中度NFκ B激活寡核苷酸mEN 101及其人直系同源物BL-7040，而不是典型的NFκB激活寡核苷酸ODN 1826，诱导抗焦虑作用。在应激小鼠中，外周给予mEN 101可预防延迟性应激诱导的血清白细胞介素-1 β升高，同时限制应激特征性海马转录物修饰和焦虑诱导的EGFR 1介导的神经元激活。BL-7040在共表达TLR 9的转染细胞中抑制NFκ B介导的荧光素酶，但不抑制其他TLRs，这证明了这种反应的TLR 9特异性。此外，TLR 9 −/−小鼠对mEN 101和BL-7040具有抗性，并表现出无端的焦虑样行为和焦虑特征性海马转录物。我们的研究结果证明了TLR 9在保护应激哺乳动物免于对创伤经历过度反应中的功能相关性，并建议使用利格列汀介导的外周TLR 9活化来增强先天免疫系统并预防创伤后炎症和焦虑。
Post-traumatic anxiety notably involves inflammation, but its causes and functional significance are yet unclear. Here, we report that failure of the innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is causally involved with anxiety-associated inflammation and that peripheral administration of specific oligonucleotide activators of TLR9 may prevent post-traumatic consequences in stressed mice. Suggesting involvement of NFκB-mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1β increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NFκB-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NFκB activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1β increases while limiting stress-characteristic hippocampal transcript modifications and the anxiety-induced EGR1-mediated neuronal activation. Attesting to the TLR9 specificity of this response, BL-7040 suppressed NFκB-mediated luciferase in transfected cells co-expressing TLR9, but not other TLRs. Furthermore, TLR9−/− mice were mEN101 and BL-7040 resistant and presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal transcripts. Our findings demonstrate functional relevance of TLR9 in protecting stressed mammals from overreacting to traumatic experiences and suggest using oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate immune system and prevent post-traumatic inflammation and anxiety.
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影响因子：
64.8
作者：
E. Potter;E. Potter;D. Behan;D. Behan;W. Fischer;E. Linton;P. Lowry;W. Vale
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影响因子：
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作者：
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作者：
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Akira, S
DOI：
10.1017/s1461145707007912
发表时间：
2008-05-01
影响因子：
4.8
作者：
Cohen, Hagit;Geva, Amir B.;Kaplan, Zeev
通讯作者：
Kaplan, Zeev