title: Simulation and Analysis of Tethering Behavior of Neutrophils with Pseudopods.
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.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America.
authors.forename: Anne D
authors.initials: AD
authors.lastname: Rocheleau
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Ronen
authors.initials: R
authors.lastname: Sumagin
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Ingrid H
authors.initials: IH
authors.lastname: Sarelius
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: King
mesh_terms: D000465:Algorithms; D002448:Cell Adhesion; D003198:Computer Simulation; D004730:Endothelium, Vascular; D036904:Leukocyte Rolling; D008954:Models, Biological; D009504:Neutrophils / Q000502:physiology*; D019087:Selectins / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: D019087:Selectins