HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling

被引:137
作者
Yang, Qing-Wu [1 ]
Lu, Feng-Lin [2 ]
Zhou, Yu [1 ]
Wang, Lin [1 ]
Zhong, Qi [1 ]
Lin, Sen [1 ]
Xiang, Jing [1 ]
Li, Jing-Cheng [1 ]
Fang, Chuan-Qing [1 ]
Wang, Jing-Zhou [1 ]
机构
[1] Third Mil Med Univ, Dept Neurol, Daping Hosp, Chongqing 400042, Peoples R China
[2] Chongqing Univ, Coll Biomed Engn, Chongqing 630044, Peoples R China
基金
中国国家自然科学基金;
关键词
acute cerebral infarct; HMGB1; ischemia-reperfusion injury; TLR4; GROUP BOX-1 PROTEIN; INFLAMMATORY RESPONSE; CEREBRAL-ISCHEMIA; NEURONAL DEATH; BRAIN-INJURY; HMGB1; ACTIVATION; TOLL-LIKE-RECEPTOR-4; CONTRIBUTES; RELEASE;
D O I
10.1038/jcbfm.2010.129
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
High-mobility group protein box-1 (HMGB1) has recently been recognized as a novel candidate in a specific upstream pathway promoting inflammation after brain ischemia. However, its downstream pathway and underlying mechanism have yet to be elucidated. The HMGB1 level in the acute cerebral infarct (ACI) group was significantly increased compared with that of control group, and correlated with the severity of neurologic impairment of ACI patients. Further, recombinant human HMGB1 (rhHMGB1) had no effect on microglia derived from mice lacking the Toll-like receptor 4 (TLR4(-/-)). Intracerebroventricular injection of rhHMGB1 in TLR4(+/+) mice cause significantly more injury after cerebral ischemia-reperfusion than control group. But, TLR4(-/-) mice administered with rhHMGB1 showed moderate impairment after ischemia-reperfusion than TLR4(+/+) mice. To determine the potential downstream signaling of HMGB1/TLR4 in cerebral ischemic injury, we used the ischemic-reperfusion model with Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-beta knockout mice (TRIF-/-) and evaluated the activity and expression of TRIF pathway-related kinases. The results suggest that the TRIF pathway is not likely to be involved in TLR4-mediated ischemia brain injury. Finally, we found that TLR4 expressed by immigrant macrophages was involved in the development of ischemic brain damage. These results suggest that HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. The TLR4 expressed by immigrant macrophages may be involved in the development of ischemic brain damage. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 593-605; doi: 10.1038/jcbfm.2010.129; published online 11 August 2010
引用
收藏
页码:593 / 605
页数:13
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