Selectin avidity modulation by chemokines at subsecond endothelial contacts: a novel regulatory level of leukocyte trafficking.

Abstract

Immune cells (leukocytes) and hematopoietic progenitor cells circulating the body must exit blood vessels near specific target sites of injury, infection, inflammation, or proliferation (Springer 1994; Butcher and Picker 1996; Mazo and von Andrian 1999). Recruitment of different subsets of leukocytes and circulating malignant cells to these sites is tightly regulated by sequential adhesive interactions between specific protein receptors on their surface and respective ligands on the blood vessel endothelial wall (Muller et al. 2001). Accumulated data from in vivo and in vitro studies suggest that the major players in this multistep process are members of two adhesive families, selectins and integrins, which are structurally and functionally adapted to operate under disruptive shear forces exerted on leukocytes at the vessel wall by the blood flow. The primary attachment or tethering of circulating leukocytes to the vessel wall is labile, mediated by specialized adhesive lectins, selectins, permitting leukocytes to roll in the direction of flow and bringing them into proximity with activating chemoattractants or chemokines on the endothelial surface (Mackay 2001). These vessel wall-displayed cytokines bind specific G-protein coupled receptors (GPCRs) on recruited leukocytes and trigger, within subseconds, the activation on the leukocyte surface of a second class of adhesion receptors, integrins, which can then firmly bind to their endothelial ligands causing the immune cell to temporarily arrest on the blood vessel (Campbell and Butcher 2000). A remarkable feature of these receptors is that their activity is dynamically regulated independent of their level of surface expression (Shimizu et al. 1999). This allows immune cells to rapidly adapt their adhesive behavior towards specific endothelial sites within target tissues accordingly to tissue-and context-restricted patterns of chemokine or chemoattractant expression at these sites.