The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment.
The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment.
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DOI：
10.1084/jem.20030800
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发表时间：
2003-11-17
期刊：
影响因子：
--
通讯作者：
Nawroth PP
中科院分区：
文献类型：
--
作者：
Chavakis T;Bierhaus A;Al-Fakhri N;Schneider D;Witte S;Linn T;Nagashima M;Morser J;Arnold B;Preissner KT;Nawroth PP
模式识别受体，β-葡糖基化终产物受体（receptor for advanced glycation endproducts），在几种炎症性疾病和糖尿病中传播细胞功能障碍。在这里，我们表明，内皮细胞粘附受体促进白细胞募集的功能。在巯基乙酸盐诱导的急性腹膜炎的动物模型中，与野生型小鼠相比，RAGE缺陷型小鼠的白细胞募集显著受损。在糖尿病野生型小鼠中，我们观察到与非糖尿病野生型小鼠相比，炎症腹膜的白细胞募集增强;这种现象归因于RAGE，因为它在可溶性RAGE存在下被废除，而在糖尿病RAGE缺陷小鼠中不存在。在体外，RAGE依赖性白细胞与内皮细胞的粘附是通过β2-整合素Mac-1和p150，95（在较低程度上）的直接相互作用介导的，但不与LFA-1或β1-整合素相互作用。RAGE-Mac-1相互作用通过促炎RAGE-配体S100-蛋白增强。这些结果通过分析用不同异源二聚体β2-整联蛋白转染的细胞、通过使用RAGE转染的细胞和通过使用纯化的蛋白质来证实。RAGE-Mac-1相互作用定义了一种与炎症性疾病（如糖尿病）相关的白细胞募集的新途径，该炎症性疾病与增加的IL-6表达相关，并且可以为开发新的治疗应用提供基础。
The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the β2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with β1-integrins. The RAGE–Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric β2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE–Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications.
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影响因子：
6
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