Filamin B mediates ICAM-1-driven leukocyte transendothelial migration.
During inflammation, the endothelium mediates rolling and firm adhesion of activated leukocytes. Integrin-mediated adhesion to endothelial ligands of the Ig-superfamily induces intracellular signaling in endothelial cells, which promotes leukocyte transendothelial migration. We identified the actin cross-linking molecule filamin B as a novel binding partner for intracellular adhesion molecule-1 (ICAM-1). Immune precipitation as well as laser scanning confocal microscopy confirmed the specific interaction and co-localization of endogenous filamin B with ICAM-1. Importantly, clustering of ICAM-1 promotes the ICAM-1-filamin B interaction. To investigate the functional consequences of filamin B binding to ICAM-1, we used small interfering RNA to reduce filamin B expression in ICAM-1-GFP expressing HeLa cells. We found that filamin B is required for the lateral mobility of ICAM-1 and for ICAM-1-induced transmigration of leukocytes. Reducing filamin B expression in primary human endothelial cells resulted in reduced recruitment of ICAM-1 to endothelial docking structures, reduced firm adhesion of the leukocytes to the endothelium, and inhibition of transendothelial migration. In conclusion, this study identifies filamin B as a molecular linker that mediates ICAM-1-driven transendothelial migration.
Kanters
Edwin
E
Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam.
van Rijssel
Jos
J
Hensbergen
Paul J
PJ
Hondius
David
D
Mul
Frederik P J
FP
Deelder
André M
AM
Sonnenberg
Arnoud
A
van Buul
Jaap D
JD
Hordijk
Peter L
PL
D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D064448:Filamins; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
D051242:Caveolin 1; D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D018799:Intercellular Adhesion Molecule-1