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

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.

Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study

“…[4][5][6] It stimulates the motility of hematopoietic cells, lymphocytes, and monocytes, 7,8 thymocytes, 9 and mediates leukocyte adhesion to the vascular endothelium. 10 SDF-1 also influences the development of microglia, astrocytes, and neurons. 11,12 CXCR4 serves as a coreceptor along with CD4 for Tcell tropic X4 HIV-1 strains.…”

Integrin αE(CD103)β7 Mediates Adhesion to Intestinal Microvascular Endothelial Cell Lines Via an E-Cadherin-Independent Interaction

“…This initial binding is, in many cases, mediated by the interaction of selectins with glycosylated ligands. For some adhesive interactions, the rolling interaction is enhanced by the presence of chemokines (2). As the lymphocyte rolls along the endothelium, chemokine receptors expressed on the T cell come into further contact with chemokines displayed within the endothelial cell glycocalyx (3).…”

Quantum Proteolytic Activation of Chemokine CCL15 by Neutrophil Granulocytes Modulates Mononuclear Cell Adhesiveness

“…Chemokines, present on the endothelial surface under physiologic or pathologic conditions (19 -22), trigger rolling and firm adhesion by activation of Gi protein-coupled receptors (23)(24)(25)(26). Tethering and rolling of leukocytes at adhesive contact zones is increased by integrin clustering raising the avidity of integrin-ligand interactions (25,(27)(28)(29). Integrin-mediated arrest of leukocytes on vascular endothelium is suggested to be induced by further interaction partners.…”

“…The subsequent recruitment of leukocytes to inflamed tissue requires their tethering and rolling as well as rapid activation of integrin-dependent arrest on the target endothelium as a checkpoint for diapedesis to the extravascular tissue (17,18). Chemokines, present on the endothelial surface under physiologic or pathologic conditions (19 -22), trigger rolling and firm adhesion by activation of Gi protein-coupled receptors (23)(24)(25)(26). Tethering and rolling of leukocytes at adhesive contact zones is increased by integrin clustering raising the avidity of integrin-ligand interactions (25,(27)(28)(29).…”