Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction
Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction
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单核细胞中Toll样受体4表达上调与急性脑梗死的严重程度相关
DOI：
10.1038/jcbfm.2008.50
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发表时间：
2008-09-01
影响因子：
6.3
通讯作者：
Wang, Jing-zhou
中科院分区：
文献类型：
--
作者：
Yang, Qing-wu;Li, Jing-cheng;Wang, Jing-zhou
在本研究中，我们观察了toll样受体4 （TLR4）及其下游信号通路在急性脑梗死（ACI）患者外周血单核细胞（PBMs）中的表达。流式细胞术和逆转录聚合酶链反应检测PBMs中TLR4和MyD88的表达，电泳迁移位移法检测核因子κ B （nf - κ B）活性。在MyD88基因敲除小鼠中测定缺血/再灌注损伤引起的脑水肿、梗死面积和神经功能损伤评分。结果表明，与对照组和短暂性缺血发作（TIA）组相比，ACI患者循环TLR4（+）单核细胞明显增加。这种变化与ACI和TIA组TLR4mRNA转录和血清肿瘤坏死因子- α (tnf - α)和白细胞介素(IL)-6的升高相似。相关分析显示TLR4表达与细胞因子水平及卒中严重程度显著相关。MyD88mRNA在三组间差异不显著。与野生型小鼠相比，MyD88基因敲除小鼠6 h脑缺血后再灌注24 h对脑水肿、脑梗死面积和神经功能损伤评分无显著影响。与对照组相比，ACI和TIA组血清热休克蛋白（HSP） 60显著升高，导致TLR4/ cd14转染的HEK293细胞NF-kappa B活化。提示ppmbs上TLR4表达上调可能是ACI后炎症损伤的外周机制之一。此外，循环HSP60可能是TLR4的配体，TLR4可能通过不依赖于myd88的信号通路参与ACI后炎症损伤的外周机制。
In the present study, we observed the expression of toll-like receptor 4 (TLR4) and its downstream signal pathway in peripheral blood monocytes (PBMs) from patients with acute cerebral infarct (ACI). The expression of TLR4 and MyD88 by PBMs was determined by flow cytometry and reverse transcriptase-polymerase chain reaction, and nuclear factor-kappa B (NF-kappa B) activity was detected by electrophoretic mobility shift assay. Ischemia/reperfusion injury-induced cerebral edema, infarction area, and neurologic impairment scores were determined in MyD88 gene knockout mice. The results indicated a significant increase in circulating TLR4(+) monocytes in ACI patients as compared with the control group and the transient ischemia attack (TIA) group. This change paralleled an elevation in TLR4mRNA transcription and serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in the ACI and TIA groups. Correlation analysis showed TLR4 expression to significantly correlate with cytokine levels and stroke severity. MyD88mRNA differed insignificantly among the three groups. Compared with wild-type mice, 6 h of cerebral ischemia followed by 24 h of reperfusion did not significantly change cerebral edema, cerebral infarction area, and neurologic impairment scores in MyD88 gene knockout mice. Compared with the control group, serum heat shock protein (HSP) 60 increased significantly in the ACI and TIA groups, leading to NF-kappa B activation in TLR4/CD14-transfected HEK293 cells. It is suggested that upregulated TLR4 expression on PMBs may act as one of the peripheral mechanisms of inflammatory injury after ACI. Moreover, circulating HSP60 may be a ligand for TLR4, which is involved in the peripheral mechanism of inflammatory injury after ACI, possibly through an MyD88-independent signal pathway.