Role of alpha4beta1 integrins in chemokine-induced monocyte arrest under conditions of shear stress.
Monocyte recruitment or emigration to tissues is an essential component of host defense in both acute and chronic inflammatory responses. Sequential molecular interactions mediate a cascade of tethering, rolling, arrest, stable adhesion, and intravascular crawling that culminates in monocyte diapedesis across the vascular endothelium and migration through the basement membrane of postcapillary venules. Integrins are complex adhesion and signaling molecules. Dynamic alterations in their conformation and distribution on the monocyte cell surface are required for many steps of monocyte emigration. Intracellular signaling initiated by chemokine receptors induces conformational changes in integrins that upregulate their affinity for ligands, and this is essential for monocyte arrest. This review focuses on the activation of monocyte alpha4beta1 integrins by endothelial chemokines, which is required for the arrest of monocytes rolling on vascular cell adhesion molecule 1 under shear flow. Using soluble ligand-binding assays and adhesion assays in parallel-plate flow chambers, critical signaling mediators in chemokine-induced alpha4beta1 integrin affinity upregulation and monocyte arrest have been identified, including phospholipase C, calcium, and calmodulin.
Hyduk
Sharon J
SJ
Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, Ontario, Canada.
Cybulsky
Myron I
MI
D000208:Acute Disease; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D018925:Chemokines / Q000378:metabolism; D002908:Chronic Disease; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D036904:Leukocyte Rolling; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D019707:Receptors, Chemokine / Q000378:metabolism; D033081:Shear Strength; D015398:Signal Transduction
D018925:Chemokines; D039041:Integrin alpha4beta1; D019707:Receptors, Chemokine