Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke
Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke
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DOI：
10.1161/circulationaha.106.603431
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发表时间：
2007-03-27
期刊：
影响因子：
37.8
通讯作者：
Lizasoain, Ignacio
中科院分区：
文献类型：
--
作者：
Caso, Javier R.;Pradillo, Jesus M.;Lizasoain, Ignacio
中风是第二到第三大死因。toll样受体4 （TLR4）是先天免疫中的一种信号受体，是对全身性细菌感染和脑损伤的特异性免疫反应。TLR4在脑缺血中的作用尚未被研究。因此，我们研究了在缺乏功能性TLR4信号通路的小鼠中，大脑中动脉永久性闭塞引起的脑缺血和炎症是否存在差异。方法与结果：对2株tlr4缺陷小鼠（C3H/HeJ和C57BL/10ScNJ）和对照组（C3H/HeN和C57BL/10ScSn）进行大脑中动脉永久性闭塞。通过测定梗死面积和评估神经学评分来评估卒中结局。脑卒中后24小时和7天分别采集脑组织。与对照组小鼠相比，tlr4缺陷小鼠的梗死体积更小，神经和行为测试结果更好。缺乏TLR4的小鼠卒中诱导干扰素调节因子-1、诱导型一氧化氮合酶和环氧化酶-2的表达较少，这些介质与脑损伤有关。在tlr4缺陷小鼠的大脑中，干扰素- β和脂质过氧化标志物丙二醛的水平也低于对照组小鼠。此外，tlr4缺陷小鼠脑卒中后，诱导和介导脑损伤的基质金属蛋白酶-9的表达也降低。结论tlr4缺陷小鼠缺血损伤后梗死程度较轻，炎症反应较弱。这些数据表明，TLR4信号和先天免疫参与脑损伤和缺血性损伤引发的炎症。
Background-Stroke is the second to third leading cause of death. Toll-like receptor 4 (TLR4) is a signaling receptor in innate immunity that is a specific immunologic response to systemic bacterial infection and cerebral injury. The role of TLR4 in brain ischemia has not been examined yet. We have therefore investigated whether cerebral ischemia and inflammation produced by permanent occlusion of the middle cerebral artery differ in mice that lack a functional TLR4 signaling pathway.Methods and Results-Permanent occlusion of the middle cerebral artery was performed on 2 strains of TLR4-deficient mice (C3H/HeJ and C57BL/10ScNJ) and respective controls (C3H/HeN and C57BL/10ScSn). Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected 24 hours and 7 days after stroke. When compared with control mice, TLR4-deficient mice had lower infarct volumes and better outcomes in neurological and behavioral tests. Mice that lacked TLR4 had minor expression of stroke-induced interferon regulatory factor-1, inducible nitric oxide synthase, and cyclooxygenase-2, mediators implicated in brain damage. The levels of interferon-beta and of the lipid peroxidation marker malondialdehyde were also lower in brains from TLR4-deficient mice than in those from control mice. In addition, the expression of matrix metalloproteinase-9, which is induced and mediates brain damage, was also reduced in TLR4-deficient mice after experimental stroke.Conclusions-TLR4-deficient mice have minor infarctions and less inflammatory response after an ischemic insult. These data demonstrate that TLR4 signaling and innate immunity are involved in brain damage and in inflammation triggered by ischemic injury.