Department of Neurosurgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
J Neurosurg. 2010 Oct;113(4):851-8. doi: 10.3171/2009.9.JNS09329.
The pathophysiological origin of cerebral aneurysms is closely associated with chronic inflammation in arterial walls. Recently, the authors identified nuclear factor-kappa B (NF-κB) as a key mediator of cerebral aneurysm formation and progression. Because Toll-like receptor 4 (TLR4) stimulates NF-κB activation in arterial walls in atherosclerosis, the authors hypothesize that TLR4 expresses in cerebral aneurysms and contributes to the activation of NF-κB in cerebral aneurysm walls.
Cerebral aneurysms were induced in male Sprague-Dawley rats. Expression of TLRs in cerebral aneurysm walls was assessed using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of TLR4 was examined using RT-PCR, immunohistochemical studies, and Western blotting. To assess TLR4 dependency on NF-κB activation, double immunostaining and a study using NF-κB-deficient mice were done. Finally, TLR4 expression in human cerebral aneurysm walls was assessed using immunohistochemical studies.
In cerebral aneurysm walls, TLR1, -4, -5, -6, -10, and -11 were expressed. Among them, TLR4 and TLR10 expression changed during cerebral aneurysm formation. Expression of TLR4 was predominantly in the endothelial cell layer of cerebral aneurysm walls, and was transitionally upregulated at the early stage of cerebral aneurysm formation. The TLR4 expression coincided well with NF-κB activation. In human cerebral aneurysms, TLR4 was also expressed in the endothelial cell layer, as it was in rats.
Toll-like receptor 4 was expressed in cerebral aneurysm walls both in rats and humans. This receptor may play a crucial role in cerebral aneurysm formation through NF-κB activation in endothelial cells. The results of the present study will shed new light on the pathogenesis of cerebral aneurysm formation.
脑动脉瘤的病理生理学起源与动脉壁的慢性炎症密切相关。最近，作者将核因子-κB（NF-κB）鉴定为脑动脉瘤形成和进展的关键介质。由于 Toll 样受体 4（TLR4）在动脉粥样硬化中刺激动脉壁中 NF-κB 的激活，作者假设 TLR4 在脑动脉瘤中表达，并有助于脑动脉瘤壁中 NF-κB 的激活。
在雄性 Sprague-Dawley 大鼠中诱导脑动脉瘤。使用逆转录聚合酶链反应（RT-PCR）评估 TLR 在脑动脉瘤壁中的表达。使用 RT-PCR、免疫组织化学研究和 Western 印迹检测 TLR4 的表达。为了评估 TLR4 对 NF-κB 激活的依赖性，进行了双重免疫染色和 NF-κB 缺陷小鼠的研究。最后，使用免疫组织化学研究评估人类脑动脉瘤壁中的 TLR4 表达。
在脑动脉瘤壁中，TLR1、-4、-5、-6、-10 和 -11 均有表达。其中，TLR4 和 TLR10 的表达在脑动脉瘤形成过程中发生变化。TLR4 的表达主要在脑动脉瘤壁的内皮细胞层中，并且在脑动脉瘤形成的早期阶段呈过渡性上调。TLR4 的表达与 NF-κB 激活非常吻合。在人类脑动脉瘤中，TLR4 也在内皮细胞层中表达，与大鼠中的表达相同。
TLR4 在大鼠和人类的脑动脉瘤壁中均有表达。该受体可能通过内皮细胞中 NF-κB 的激活在脑动脉瘤形成中发挥关键作用。本研究的结果将为脑动脉瘤形成的发病机制提供新的线索。
