RAGE and ICAM-1 cooperate in mediating leukocyte recruitment during acute inflammation in vivo

• Published in: Blood Vol. 116; no. 5; pp. 841 - 849
• Main Authors: Frommhold, David, Kamphues, Anna, Hepper, Ingrid, Pruenster, Monika, Lukić, Ivan K., Socher, Ines, Zablotskaya, Victoria, Buschmann, Kirsten, Lange-Sperandio, Baerbel, Schymeinsky, Jürgen, Ryschich, Eduard, Poeschl, Johannes, Kupatt, Christian, Nawroth, Peter P., Moser, Markus, Walzog, Barbara, Bierhaus, Angelika, Sperandio, Markus
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 05-08-2010; Americain Society of Hematology
• Subjects: Acute Disease; Animals; Biological and medical sciences; Cell Adhesion; Cell Shape; Chemotaxis, Leukocyte - drug effects; Chemotaxis, Leukocyte - physiology; Endothelium, Vascular - metabolism; Hematologic and hematopoietic diseases; Humans; Intercellular Adhesion Molecule-1 - physiology; Leukotriene B4 - pharmacology; Ligands; Macrophage-1 Antigen - metabolism; Medical sciences; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases - deficiency; Mitogen-Activated Protein Kinases - physiology; Muscle, Skeletal - blood supply; Muscle, Skeletal - injuries; Muscle, Skeletal - pathology; Neutrophils - pathology; Radiation Chimera; Recombinant Fusion Proteins - physiology; Tumor Necrosis Factor-alpha - pharmacology; Vasculitis - etiology; Vasculitis - immunology; Venules - pathology; In vivo; Tumor associated antigen; Hematology; Intercellular adhesion molecule 1; Leukocyte; Acute; Cell adhesion molecule; Inflammation; Recruitment
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-09-244293

The receptor for advanced glycation end products (RAGE) contributes to the inflammatory response in many acute and chronic diseases. In this context, RAGE has been identified as a ligand for the β2-integrin Mac-1 under static in vitro conditions. Because intercellular adhesion molecule (ICAM)-1 also binds β2-integrins, we studied RAGE−/−, Icam1−/−, and RAGE−/−Icam1−/− mice to define the relative contribution of each ligand for leukocyte adhesion in vivo. We show that trauma-induced leukocyte adhesion in cremaster muscle venules is strongly dependent on RAGE and ICAM-1 acting together in an overlapping fashion. Additional in vivo experiments in chimeric mice lacking endothelium-expressed RAGE and ICAM-1 located the adhesion defect to the endothelial compartment. Using microflow chambers coated with P-selectin, CXCL1, and soluble RAGE (sRAGE) demonstrated that sRAGE supports leukocyte adhesion under flow conditions in a Mac-1– but not LFA-1–dependent fashion. A static adhesion assay revealed that wild-type and RAGE−/− neutrophil adhesion and spreading were similar on immobilized sRAGE or fibrinogen. These observations indicate a crucial role of endothelium-expressed RAGE as Mac-1 ligand and uncover RAGE and ICAM-1 as a new set of functionally linked adhesion molecules, which closely cooperate in mediating leukocyte adhesion during the acute trauma-induced inflammatory response in vivo.