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

2010; Elsevier BV; Volume: 116; Issue: 5 Linguagem: Inglês

10.1182/blood-2009-09-244293

1528-0020

David Frommhold, Anna Kamphues, Ingrid Hepper, Monika Pruenster, Ivan Krešimir Lukić, Ines Socher, Victoria Zablotskaya, Kirsten Buschmann, Baerbel Lange‐Sperandio, Jürgen Schymeinsky, Eduard Ryschich, Johannes Poeschl, Christian Kupatt, Peter P. Nawroth, Markus Moser, Barbara Walzog, Angelika Bierhaus, Markus Sperandio,

S100 Proteins and Annexins

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.