Subsecond induction of alpha4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule 1 under flow conditions

V Grabovsky, S Feigelson, C Chen, D A Bleijs, A Peled, G Cinamon, F Baleux, F Arenzana-Seisdedos, T Lapidot, Yvette van Kooyk Y, R R Lobb, R Alon

Research output: Contribution to journalArticleAcademicpeer-review

290 Citations (Scopus)

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, alpha4beta1), 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.

Original languageEnglish
Pages (from-to)495-506
Number of pages12
JournalJournal of Experimental Medicine
Volume192
Issue number4
Publication statusPublished - 21 Aug 2000

Keywords

  • Antibodies, Monoclonal
  • Cell Adhesion/physiology
  • Cell Movement/physiology
  • Cells, Cultured
  • Chemokine CXCL12
  • Chemokines, CXC/metabolism
  • Endothelium, Vascular/cytology
  • Flow Cytometry
  • Humans
  • Integrin alpha4beta1
  • Integrins/metabolism
  • Leukocytes/metabolism
  • Microscopy, Confocal
  • Microscopy, Video
  • Receptors, Lymphocyte Homing/metabolism
  • Signal Transduction
  • T-Lymphocytes/metabolism
  • Tetradecanoylphorbol Acetate/pharmacology
  • Tumor Necrosis Factor-alpha/pharmacology
  • Vascular Cell Adhesion Molecule-1/genetics

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