RAGE and ICAM-1 cooperate in mediating leukocyte recruitment during acute inflammation in vivo.
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.
Frommhold
David
D
Section of Neonatal Medicine, University of Heidelberg, Heidelberg, Germany.
Kamphues
Anna
A
Hepper
Ingrid
I
Pruenster
Monika
M
Lukic
Ivan K
IK
Socher
Ines
I
Zablotskaya
Victoria
V
Buschmann
Kirsten
K
Lange-Sperandio
Baerbel
B
Schymeinsky
Jürgen
J
Ryschich
Eduard
E
Poeschl
Johannes
J
Kupatt
Christian
C
Nawroth
Peter P
PP
Moser
Markus
M
Walzog
Barbara
B
Bierhaus
Angelika
A
Sperandio
Markus
M
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
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