The Journal of Experimental Medicine
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Published 17 November 2003. doi:10.1084/jem.20030800
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© Rockefeller University Press, 0022-1007/2003/11/1507 $5.00
The Journal of Experimental Medicine, Volume 198, Number 10, 1507-1515

The Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins : A Novel Pathway for Inflammatory Cell Recruitment



Triantafyllos Chavakis1, Angelika Bierhaus1, Nadia Al-Fakhri5, Darius Schneider3, Steffen Witte2, Thomas Linn3, Mariko Nagashima7, John Morser7, Bernd Arnold6, Klaus T. Preissner4 and Peter P. Nawroth1

1 Department of Internal Medicine I, University Heidelberg, D-69115 Heidelberg, Germany
2 Institute for Medical Biometry and Informatics, University Heidelberg, D-69120 Heidelberg, Germany
3 Third Department of Internal Medicine, Justus-Liebig-University, D-35392 Giessen, Germany
4 Institute for Biochemistry, Justus-Liebig-University, D-35392 Giessen, Germany
5 Institute for Clinical Chemistry, Justus-Liebig-University, D-35392 Giessen, Germany
6 Department of Molecular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany
7 Berlex Biosciences, Richmond, CA 94806

Address correspondence to Dr. T. Chavakis, Department of Internal Medicine I, University Heidelberg, Bergheimer Strasse 58, D-69115 Heidelberg, Germany. Phone: 49-6221-5638603; Fax: 49-6221-564101. email: triantafyllos.chavakis{at}med.uni-heidelberg.de

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 ß2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with ß1-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 ß2-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.

Key Words: leukocyte • integrin • RAGE • diabetes • adhesion


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