Activation of polymorphonuclear leukocytes reduces their adhesion to P-selectin and causes redistribution of ligands for P-selectin on their surfaces.

Abstract

In acute inflammatory responses, selectins mediate initial rolling of neutrophils (PMNs) along the endothelial surface. This is followed by tight adhesion that requires activationdependent up-regulation of CD11/CD18 integrins on PMNs.For emigration to occur, the initial bonds that are established at the endothelial surface must be disengaged. We show that activation of PMNs results in their detachment from P-selectin, a glycoprotein expressed at the surface of inflamed endothelium that mediates initial tethering of PMNs. Loosening of the bond occurs when PMNs are activated by platelet-activating factor, which is coexpressed with P-selectin, or by other signaling molecules. The time course of reduced adhesion to P-selectin, when compared to up-regulation of CD11/CD18 integrins, suggests that "bond trading" may occur as activated PMNs transmigrate in vivo. Activation of PMNs did not alter binding of fluid-phase Pselectin, indicating that the ligand(s) for P-selectin is not shed or internalized. Using microspheres coated with P-selectin, we found that ligands for P-selectin were randomly distributed over the surfaces of rounded, unactivated PMNs. An antibody against P-selectin glycoprotein ligand-1 (PSGL-1) completely inhibited binding of P-selectin-coated beads suggesting that P-selectin glycoprotein ligand-1 is the critical binding site in this assay. In contrast to the dispersed pattern on unactivated PMNs, the ligands for P-selectin were localized on the uropods of activated, polarized cells. Pretreating PMNs with cytochalasin D before activation prevented the change in cell shape, the redistribution of binding sites for P-selectin-coated beads, and the decrease in cellular adhesiveness for P-selectin. These experiments indicate that the distribution of ligands for P-selectin is influenced by cellular activation and by cytoskeletal interactions, and that redistribution of these ligands may influence adhesive interactions. Activation of PMNs may cause loosenAddress correspondence to Diane E.

SELPLG Gene Polymorphisms in Relation to Plasma SELPLG Levels and Coronary Artery Disease

“…Our study failed to demonstrate any association between plasma SELPLG levels and CAD risk. It has been suggested that the way SELPLG is distributed on the leukocyte surface, and not the amount, is important for adhesion of leukocytes to P-selectin (Bruehl et al 1997;Lorant et al 1995). Moreover, SELPLG in the circulation could derive either from the release of SELPLG from leukocyte surfaces or from its release after the initiation of leukocyte rolling (Davenpeck et al 2000).…”

SLIC‐1/sorting nexin 20: A novel sorting nexin that directs subcellular distribution of PSGL‐1

“…Third, the cytoplasmic tail of PSGL-1 may contain determinants that target PSGL-1 to specific cell membrane domains. In resting leukocytes, PSGL-1 is restricted to the tips of microvilli, which facilitates its binding to selectins on other cells [15][16][17]. Despite the importance of these molecular and cellular functions mediated by the cytoplasmic domain of PSGL-1, the complete set of intracellular molecules that bind to the PSGL-1 cytoplasmic domain remain to be identified.…”

NSAIDs upregulate β2‐integrin expression on human neutrophils through a calcium‐dependent pathway

“…The mechanism(s) by which indomethacin causes myeloperoxidase release from azurophil granules is unlikely to be related to Ca 2+ mobilization. 44 In fact, the EC 50 of 680 nM required to trigger myeloperoxidase release by human PMN is at least 2±3-fold higher than the levels of Ca 2+ transients induced by indomethacin. One possible explanation for this effect is that exposure to indomethacin activates other intracellular messengers (e.g.…”