title: RAGE and ICAM-1 cooperate in mediating leukocyte recruitment during acute inflammation in vivo.
abstract: 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 beta(2)-integrin Mac-1 under static in vitro conditions. Because intercellular adhesion molecule (ICAM)-1 also binds beta(2)-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.
authors.affiliation: Section of Neonatal Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Frommhold
authors.forename: Anna
authors.initials: A
authors.lastname: Kamphues
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hepper
authors.forename: Monika
authors.initials: M
authors.lastname: Pruenster
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Lukic
authors.forename: Ines
authors.initials: I
authors.lastname: Socher
authors.forename: Victoria
authors.initials: V
authors.lastname: Zablotskaya
authors.forename: Kirsten
authors.initials: K
authors.lastname: Buschmann
authors.forename: Baerbel
authors.initials: B
authors.lastname: Lange-Sperandio
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schymeinsky
authors.forename: Eduard
authors.initials: E
authors.lastname: Ryschich
authors.forename: Johannes
authors.initials: J
authors.lastname: Poeschl
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Barbara
authors.initials: B
authors.lastname: Walzog
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
mesh_terms: D000208:Acute Disease; D000818:Animals; D002448:Cell Adhesion; D048430:Cell Shape; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007975:Leukotriene B4 / Q000494:pharmacology; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000502:physiology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000293:injuries / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014657:Vasculitis / Q000209:etiology / Q000276:immunology*; D014699:Venules / Q000473:pathology
chemical_list: D008024:Ligands; D016177:Macrophage-1 Antigen; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007975:Leukotriene B4; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases