HMBG1 Mediates Ischemia—Reperfusion Injury by TRIF-Adaptor Independent Toll-Like Receptor 4 Signaling
HMBG1 Mediates Ischemia—Reperfusion Injury by TRIF-Adaptor Independent Toll-Like Receptor 4 Signaling
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DOI：
10.1038/jcbfm.2010.129
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发表时间：
2011-02
影响因子：
6.3
通讯作者：
Qing-Wu Yang;F. Lu;Yu Zhou;Lin Wang;Qi Zhong;Sen Lin;Jing Xiang;Jing-cheng Li;Chuanqin Fang;Jing-zhou Wang
中科院分区：
文献类型：
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作者：
Qing-Wu Yang;F. Lu;Yu Zhou;Lin Wang;Qi Zhong;Sen Lin;Jing Xiang;Jing-cheng Li;Chuanqin Fang;Jing-zhou Wang
高迁移率族蛋白盒-1（HMGB 1）最近被认为是脑缺血后促进炎症的特异性上游通路的新候选者。然而，其下游途径和潜在机制尚未阐明。急性脑梗死组HMGB 1水平较对照组明显升高，且与脑梗死患者神经功能缺损程度相关。此外，重组人HMGB 1（rhHMGB 1）对来自缺乏Toll样受体4（TLR 4 −/-）的小鼠的小胶质细胞没有影响。侧脑室注射rhHMGB 1对TLR 4 +/+小鼠脑缺血再灌注损伤明显加重。但是，与TLR 4 +/+小鼠相比，给予rhHMGB 1的TLR 4-/-小鼠在缺血再灌注后表现出中度损伤。为了确定HMGB 1/TLR 4在脑缺血损伤中的潜在下游信号传导，我们使用了Toll/白细胞介素-1受体结构域含有衔接子诱导的干扰素-β基因敲除小鼠（TRIF−/-）的缺血再灌注模型，并评估了TRIF途径相关激酶的活性和表达。结果表明TRIF通路不太可能参与TLR 4介导的缺血性脑损伤。最后，我们发现迁移巨噬细胞表达的TLR 4参与了缺血性脑损伤的发生。这些结果表明，HMBG 1介导的缺血再灌注损伤的TRIF接头非依赖性Toll样受体4信号。迁移巨噬细胞表达的TLR 4可能参与缺血性脑损伤的发生发展。
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-β 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.