Resolving postoperative neuroinflammation and cognitive decline.
Resolving postoperative neuroinflammation and cognitive decline.
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DOI：
10.1002/ana.22664
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发表时间：
2011-12
影响因子：
11.2
通讯作者：
Maze M
中科院分区：
文献类型：
--
作者：
Terrando N;Eriksson LI;Ryu JK;Yang T;Monaco C;Feldmann M;Jonsson Fagerlund M;Charo IF;Akassoglou K;Maze M
认知能力下降伴随着急性疾病和手术，尤其是在老年人。手术会激活先天免疫系统，引发全身性炎症反应，如果不加以控制，可能会导致多器官功能障碍。我们试图了解炎症反应针对大脑的机制，以及如何解决这一问题。C57BL/6J、Ccr2RFP/+Cx3cr1GFP/+、IkkF/F小鼠和LysM-Cre/IkkF/F小鼠在全麻下行胫骨稳定性骨折手术。对不同的小鼠队列进行了全身和海马区炎症、血脑屏障(BBB)完整性和认知能力的测试。我们还研究了胆碱能通路对这些术后反应的假定消解作用。外周手术通过释放肿瘤坏死因子α来破坏血脑屏障，促进巨噬细胞向海马区的迁移。巨噬细胞特异性地删除IKKβ，通过激活NF-αB来调节肿瘤坏死因子κ信号的中心协调者，可以防止手术后血脑屏障的破坏和巨噬细胞在海马区的渗透。α7亚型烟碱型乙酰胆碱受体的激活是一种内源性炎症化解途径，可防止肿瘤坏死因子α诱导的核因子-κB激活、巨噬细胞迁移到海马区和手术后认知功能下降。这些数据揭示了无菌创伤后大脑和免疫系统之间双向交流的机制。关键的分子机制可以靶向预防和/或解决术后神经炎症和认知功能下降。
Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response which, if unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved. C57BL/6J, Ccr2RFP/+ Cx3cr1GFP/+, IkkF/F mice and LysM-Cre/IkkF/F underwent stabilized tibial fracture operation under analgesia and general anesthesia. Separate cohorts of mice were tested for systemic and hippocampal inflammation, integrity of the blood brain barrier (BBB), and cognition. The putative resolving effects of the cholinergic pathway on these postoperative responses were also studied. Peripheral surgery disrupts the BBB via release of tumor necrosis factor-alpha (TNFα), which facilitates the migration of macrophages into the hippocampus. Macrophage-specific deletion of IKKβ, a central coordinator of TNFα signaling through activation of NF-κB, prevents BBB disruption and macrophage infiltration in the hippocampus following surgery. Activation of the α7 subtype of nicotinic acetylcholine receptors, an endogenous inflammation-resolving pathway, prevents TNFα-induced NF-κB activation, macrophage migration into the hippocampus and cognitive decline following surgery. These data reveal the mechanisms for bidirectional communication between the brain and immune system following aseptic trauma. Pivotal molecular mechanisms can be targeted to prevent and/or resolve postoperative neuroinflammation and cognitive decline.