Novel chemokine functions in lymphocyte migration through vascular endothelium under shear flow.
The recruitment of circulating leukocytes at vascular sites in target tissue has been linked to activation of Gi-protein signaling in leukocytes by endothelial chemokines. The mechanisms by which apical and subendothelial chemokines regulate leukocyte adhesion to and migration across endothelial barriers have been elusive. We recently found that endothelial chemokines not only stimulate integrin-mediated arrest on vascular endothelial ligands but also trigger earlier very late antigen (VLA)-4 integrin-mediated capture (tethering) of lymphocytes to vascular cell adhesion molecule 1 (VCAM-1)-bearing surfaces by extremely rapid modulation of integrin clustering at adhesive contact zones. This rapid modulation of integrin avidity requires chemokine immobilization in juxtaposition with the VLA-4 ligand VCAM-1. We also observed that endothelial-bound chemokines promote massive lymphocyte transendothelial migration (TEM). It is interesting that chemokine-promoted lymphocyte TEM requires continuous exposure of lymphocytes but not of the endothelial barrier to fluid shear. It is noteworthy that lymphocyte stimulation by soluble chemokines did not promote lymphocyte TEM. Our results suggest new roles for apical endothelial chemokines both in triggering lymphocyte capture to the endothelial surface and in driving post-arrest events that promote lymphocyte transmigration across endothelial barriers under shear flow.
Cinamon
G
G
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Grabovsky
V
V
Winter
E
E
Franitza
S
S
Feigelson
S
S
Shamri
R
R
Dwir
O
O
Alon
R
R
D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D002630:Chemotactic Factors / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D007249:Inflammation; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D008954:Models, Biological; D019707:Receptors, Chemokine / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D012212:Rheology; D015398:Signal Transduction; D013314:Stress, Mechanical; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D039041:Integrin alpha4beta1; D016023:Integrins; D019707:Receptors, Chemokine; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D019206:GTP-Binding Protein alpha Subunits, Gi-Go