Chavakis Triantafyllos, Bierhaus Angelika, Al-Fakhri Nadia, Schneider Darius, Witte Steffen, Linn Thomas, Nagashima Mariko, Morser John, Arnold Bernd, Preissner Klaus T, Nawroth Peter P
Department of Internal Medicine I, University Heidelberg, Bergheimer Strasse 58, D-69115 Heidelberg, Germany.
J Exp Med. 2003 Nov 17;198(10):1507-15. doi: 10.1084/jem.20030800.
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 beta2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with beta1-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 beta2-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.
模式识别受体RAGE（晚期糖基化终产物受体）在多种炎症性疾病和糖尿病中引发细胞功能障碍。在此我们表明，RAGE作为一种内皮黏附受体促进白细胞募集。在硫代乙醇酸盐诱导的急性腹膜炎动物模型中，与野生型小鼠相比，RAGE缺陷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加；这种现象归因于RAGE，因为在可溶性RAGE存在时这种现象消失，且在糖尿病RAGE缺陷小鼠中不存在。在体外，RAGE依赖的白细胞与内皮细胞的黏附是由RAGE与β2整合素Mac-1直接相互作用介导的，在较低程度上与p150,95相互作用，但不与LFA-1或β1整合素相互作用。促炎RAGE配体S100蛋白增强了RAGE-Mac-1的相互作用。通过分析用不同异源二聚体β2整合素转染的细胞、使用RAGE转染细胞以及使用纯化蛋白，这些结果得到了证实。RAGE-Mac-1相互作用定义了一条在与RAGE表达增加相关的炎症性疾病（如糖尿病）中白细胞募集的新途径，并可为新型治疗应用的开发提供基础。
