Abstract
P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) play important roles in mediating the inflammatory cascade. Selectin kinetics, together with neutrophil hydrodynamics, regulate the fundamental adhesion cascade of cell tethering and rolling on the endothelium. The current study uses the Multiscale Adhesive Dynamics computational model to simulate, for the first time, the tethering and rolling behavior of pseudopod-containing neutrophils as mediated by P-selectin/PSGL-1 bonds. This paper looks at the effect of including P-selectin/PSGL-1 adhesion kinetics. The parameters examined included the shear rate, adhesion on-rate, initial neutrophil position, and receptor number sensitivity. The outcomes analyzed included types of adhesive behavior observed, tether rolling distance and time, number of bonds formed during an adhesive event, contact area, and contact time. In contrast to the hydrodynamic model, P-selectin/PSGL-1 binding slows the neutrophil’s translation in the direction of flow and causes the neutrophil to swing around perpendicular to flow. Several behaviors were observed during the simulations, including tethering without firm adhesion, tethering with downstream firm adhesion, and firm adhesion upon first contact with the endothelium. These behaviors were qualitatively consistent with in vivo data of murine neutrophils with pseudopods. In the simulations, increasing shear rate, receptor count, and bond formation rate increased the incidence of firm adhesion upon first contact with the endothelium. Tethering was conserved across a range of physiological shear rates and was resistant to fluctuations in the number of surface PSGL-1 molecules. In simulations where bonding occurred, interaction with the side of the pseudopod, rather than the tip, afforded more surface area and greater contact time with the endothelial wall.
Highlights
During inflammation, tissue mediators release cytokines that attract free-flowing neutrophils in the bloodstream
With P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) adhesion, the neutrophil’s translation in the xdirection is slowed down as there is more pushing of the pseudopod prior to flipping (Fig 3A)
We have developed a three-dimensional computational model of a neutrophil with long pseudopod interacting with the endothelium under flow via PSGL-1/P-selectin catch-bond kinetics
Summary
Tissue mediators release cytokines that attract free-flowing neutrophils in the bloodstream. This causes neutrophils to tether and roll on the endothelium lining blood vessels before extravasating into the inflamed site [1]. Selectins mediate the capture of freeflowing neutrophils to the inflamed blood vessels. Simulation of Tethering Behavior of Neutrophils with Pseudopods glycoproteins that includes E-, L- and P-selectin. PSGL-1, concentrated on the tips of surface protrusions called microvilli [4], accounts for 90% of P-selectin binding [2]. The structure of PSGL-1 includes an N-terminal tyrosine sulfate, a long glycoprotein backbone, a transmembrane protein, and a short cytoplasmic tail [2]. Cell adhesion is increased when the thickness of the glycocalyx lining the endothelium is lessened [5]
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