Original Article

Subsecond Induction of 4 Integrin Clustering by Immobilized Chemokines Stimulates Leukocyte Tethering and Rolling on Endothelial Vascular Cell Adhesion Molecule 1 under Flow Conditions

Correspondence to: Ronen Alon, Dept. of Immunology, The Weizmann Institute of Science, Rehovot, 76100 Israel. Tel:972-8-9342482 Fax:972-8-9344141 E-mail:ronalon{at}weizmann.weizmann.ac.il.

Leukocyte recruitment to target tissue is initiated by weak rolling attachments to vessel wall ligands followed by firm integrin-dependent arrest triggered by endothelial chemokines. We show here that immobilized chemokines can augment not only arrest but also earlier integrin-mediated capture (tethering) of lymphocytes on inflamed endothelium. Furthermore, when presented in juxtaposition to vascular cell adhesion molecule 1 (VCAM-1), the endothelial ligand for the integrin very late antigen 4 (VLA-4, 4ß1), chemokines rapidly augment reversible lymphocyte tethering and rolling adhesions on VCAM-1. Chemokines potentiate VLA-4 tethering within <0.1 s of contact through Gi protein signaling, the fastest inside-out integrin signaling events reported to date. Although VLA-4 affinity is not altered upon chemokine signaling, subsecond VLA-4 clustering at the leukocyte-substrate contact zone results in enhanced leukocyte avidity to VCAM-1. Endothelial chemokines thus regulate all steps in adhesive cascades that control leukocyte recruitment at specific vascular beds.

Key Words: adhesion, integrin, endothelium, chemokine, shear flow

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• Chigaev, A., Blenc, A. M., Braaten, J. V., Kumaraswamy, N., Kepley, C. L., Andrews, R. P., Oliver, J. M., Edwards, B. S., Prossnitz, E. R., Larson, R. S., Sklar, L. A. (2001). Real Time Analysis of the Affinity Regulation of alpha 4-Integrin. THE PHYSIOLOGICALLY ACTIVATED RECEPTOR IS INTERMEDIATE IN AFFINITY BETWEEN RESTING AND Mn2+ OR ANTIBODY ACTIVATION. J. Biol. Chem. 276: 48670-48678 [Abstract] [Full Text]  

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