Subsecond Induction of α4 Integrin Clustering by Immobilized Chemokines Stimulates Leukocyte Tethering and Rolling on Endothelial Vascular Cell Adhesion Molecule 1 under Flow Conditions

Author:

Grabovsky Valentin1,Feigelson Sara1,Chen Chun1,Bleijs Diederik A.2,Peled Amnon1,Cinamon Guy1,Baleux Francoise3,Arenzana-Seisdedos Frenando3,Lapidot Tsvee1,van Kooyk Yvette2,Lobb Roy R.4,Alon Ronen1

Affiliation:

1. Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100 Israel

2. Department of Tumor Immunology, University Hospital Nijmegen, Nijmegen 6525 EX, The Netherlands

3. Unite d'Immunologie Virale, Institute Pasteur, 75724 Paris, France

4. Biogen, Incorporated, Cambridge, Massachusetts 02142

Abstract

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, α4β1), 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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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