Chemokine induction of integrin adhesiveness on rolling and arrested leukocytes local signaling events or global stepwise activation?
The arrest of rolling leukocytes on target endothelium is predominantly mediated by integrins, which pre-exist in largely inactive states on circulating immune cells and need to be activated in situ. These adhesion receptors acquire high avidity upon encounter with endothelial-displayed chemokines or chemoattractants, which are ligands to specific G protein-coupled receptors (GPCRs) on the leukocyte surface. In order to arrest, the leukocyte must constantly integrate endothelial-based signals as it moves along the vessel wall. It is unclear whether the chemokine signal is locally transmitted at the endothelial contact zone or whether the rolling leukocyte accumulates successive chemokine signals to reach a threshold global activation. Recent in vitro and in vivo data suggest that the induction of high integrin avidity by endothelial chemokine-transduced G(i)-signals is a general mechanism that has evolved to locally enhance integrin avidity to ligand within subseconds at restricted leukocyte-endothelial contacts. In addition, a second specialized mechanism, involving stepwise signals integrated by selectin ligands on rolling cells, seems to activate integrins on the entire leukocyte surface. This GPCR-independent and much slower pathway (10(1)-10(2) seconds) is transmitted through rolling engagements of neutrophils, primarily on E-selectin. We propose that these two mechanisms are differentially used by distinct leukocyte subsets at various vascular beds, providing much larger combinatorial diversity of integrin activation on rolling leukocytes than previously predicted.
Alon
Ronen
R
Department of Immunology, Weizmann Institute of Science, Rehovot, 76100 Israel. ronalon@wicc.weizmann.ac.il
Grabovsky
Valentin
V
Feigelson
Sara
S
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D018925:Chemokines / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D036904:Leukocyte Rolling / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D018925:Chemokines; D016023:Integrins