The HMGB1 receptor RAGE mediates ischemic brain damage.
The HMGB1 receptor RAGE mediates ischemic brain damage.
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DOI：
10.1523/jneurosci.2435-08.2008
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发表时间：
2008-11-12
期刊：
影响因子：
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通讯作者：
Schwaninger M
中科院分区：
文献类型：
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作者：
Muhammad S;Barakat W;Stoyanov S;Murikinati S;Yang H;Tracey KJ;Bendszus M;Rossetti G;Nawroth PP;Bierhaus A;Schwaninger M
在缺血性中风中，坏死核心被炎症区包围，其中延迟的细胞死亡加重了最初的损伤。在这里，我们提供的证据表明，晚期糖基化终末产物（AGEs）受体作为坏死细胞死亡的传感器，并有助于炎症和缺血性脑损伤。在脑缺血小鼠模型中，脑卒中患者血清中高迁移率族蛋白1（HMGB 1）水平升高，并从缺血脑组织中释放。中和性抗HMGB 1抗体和HMGB 1盒A（HMGB 1受体拮抗剂）可改善缺血性脑损伤。有趣的是，基因缺陷和可溶性诱饵受体减少了梗死面积。在体外，表达HMGB 1的小胶质细胞介导了HMGB 1的毒性作用。向神经培养物中添加巨噬细胞进一步增强了HMGB 1的毒性作用。为了测试缺血性脑中的移民巨噬细胞是否介导了骨髓抑制效应，我们通过将骨髓-/-移植到野生型小鼠中来产生嵌合小鼠。骨髓源性细胞中β 2受体缺乏显著减少了梗死面积。因此，HMGB 1-β信号转导将坏死与巨噬细胞活化联系起来，并可能为中风的抗炎治疗提供靶点。
In ischemic stroke, the necrotic core is surrounded by a zone of inflammation, in which delayed cell death aggravates the initial insult. Here, we provide evidence that the receptor for advanced glycation end products (RAGE) functions as a sensor of necrotic cell death and contributes to inflammation and ischemic brain damage. The RAGE ligand high mobility group box 1 (HMGB1) was elevated in serum of stroke patients and was released from ischemic brain tissue in a mouse model of cerebral ischemia. A neutralizing anti-HMGB1 antibody and HMGB1 box A, an antagonist of HMGB1 at the receptor RAGE, ameliorated ischemic brain damage. Interestingly, genetic RAGE deficiency and the decoy receptor soluble RAGE reduced the infarct size. In vitro, expression of RAGE in (micro)glial cells mediated the toxic effect of HMGB1. Addition of macrophages to neural cultures further enhanced the toxic effect of HMGB1. To test whether immigrant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE−/− bone marrow to wild-type mice. RAGE deficiency in bone marrow-derived cells significantly reduced the infarct size. Thus, HMGB1–RAGE signaling links necrosis with macrophage activation and may provide a target for anti-inflammatory therapy in stroke.