The Effect of P-Selectin Dimers on Neutrophil Rolling on Endothelium

Abstract

In inflammation, endothelial cells release adhesion molecules that mediate rolling of neutrophils. While rolling, neutrophils activate to become capable of firmly adhering to endothelial cells; after this, they migrate through the blood vessel wall into inflamed tissue. The initial phase of rolling, dominated by P-selectin-PSGL-1 bonds, is critical for preventing neutrophils from leaving the area of the inflammation prior to activating. A portion of endothelial P-selectin are expressed as dimers, and PSGL-1 are predominantly dimeric; however, monomeric P-selectin is typically used in in vitro studies and computational models of neutrophil rolling have not accounted for dimeric P-selectin. Prior to inflammation, P-selectin is stored in Weibel-Palade bodies located primarily near the boundaries between endothelial cells; secreted P-selectin mostly remains near these boundaries. It has been proposed that endothelial cells release a combination of monomeric and dimeric P-selectin, with dimeric P-selectin more stably binding neutrophils at endothelial cell boundaries, while the more diffusible monomeric P-selectin cover the center of the endothelial cell face. Here, a computational model of neutrophil rolling on endothelium is used to study the effects of distributions of monomeric and dimeric P-selectin on neutrophil rolling. Even small fractions of dimeric P-selectin greatly reduce neutrophil rolling velocity. Results are presented regarding the advantages of a mixed population of monomeric and dimeric P-selectin, the mechanics of force distribution across the neutrophil body, and how effectively neutrophils are attracted to endothelial cell boundaries.