Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier
Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier
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DOI：
10.4049/jimmunol.0803013
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发表时间：
2009-05-01
影响因子：
4.4
通讯作者：
Chen, Yu-Hua
中科院分区：
文献类型：
--
作者：
Li, Man;Shang, De-Shu;Chen, Yu-Hua
在阿尔茨海默病（AD）中，循环T细胞是如何渗入大脑的尚不清楚。我们之前报道了淀粉样蛋白β (A β)依赖性CCR5在脑内皮细胞中的表达参与了T细胞的跨内皮迁移。在本研究中，我们探索了A β上调CCR5的信号通路。我们发现JNK、ERK和PI3K抑制剂显著降低A β诱导的人脑微血管内皮细胞（HBMECs）中CCR5的表达。染色质免疫沉淀实验显示，A β激活的JNK、ERK和PI3K通过转录因子Egr-1促进脑内皮细胞CCR5的表达。此外，中和晚期糖基化终产物受体（RAGE，一种A β受体）的Ab有效阻断了A β诱导的JNK、ERK和PI3K的激活，促进了hbmec中CCR5的表达。当截断的RAGE在hbmec中过表达时，A β不能诱导CCR5表达。跨内皮迁移实验显示，抗RAGE Ab、过表达截断的RAGE以及PI3K、JNK/ERK、Egr-1 RNA的显性阴性干扰分别有效阻断了表达CCR5配体MIP-1 α的AD患者T细胞通过体外血脑屏障模型的迁移。重要的是，阻断脑内RAGE可消除大鼠海马A β注射诱导的CCR5对脑内皮细胞的上调和脑内T细胞浸润的增加。我们的研究结果表明，脑内A β与血脑屏障RAGE的相互作用上调了内皮细胞CCR5的表达，并导致AD患者脑内循环T细胞浸润。本研究可能为了解炎症在阿尔茨海默病进展中的作用提供新的见解。中华免疫学杂志，2009,32(2):578 - 588。
How circulating T cells infiltrate into the brain in Alzheimer disease (AD) remains unclear. We previously reported that amyloid beta (A beta)-dependent CCR5 expression in brain endothelial cells is involved in T cell transendothelial migration. In this study, we explored the signaling pathway of CCR5 up-regulation by A beta. We showed that inhibitors of JNK, ERK, and PI3K significantly decreased A beta-induced CCR5 expression in human brain microvascular endothelial cells (HBMECs). Chromatin immunoprecipitation assay revealed that A beta-activated JNK, ERK, and PI3K promoted brain endothelial CCR5 expression via transcription factor Egr-1. Furthermore, neutralization Ab of receptor for advanced glycation end products (RAGE; an A beta receptor) effectively blocked A beta-induced JNK, ERK, and PI3K activation, contributing to CCR5 expression in HBMECs. A beta fails to induce CCR5 expression when truncated RAGE was overexpressed in HBMECs. Transendothelial migration assay showed that the migration of MIP-1 alpha (a CCR5 ligand)-expressing AD patients' T cells through in vitro blood-brain barrier model was effectively blocked by anti-RAGE Ab, overexpression of truncated RAGE, and dominant-negative PI3K, JNK/ERK, or Egr-1 RNA interference in HBMECs, respectively. Importantly, blockage of intracerebral RAGE abolished the up-regulation of CCR5 on brain endothelial cells and the increased T cell infiltration in the brain induced by A beta injection in rat hippocampus. Our results suggest that intracerebral A beta interaction with RAGE at BBB up-regulates endothelial CCR5 expression and causes circulating T cell infiltration in the brain in AD. This study may provide a new insight into the understanding of inflammation in the progress of AD. The Journal of Immunology, 2009, 182: 5778-5788.