title: Adhesive dynamics simulation of G-protein-mediated chemokine-activated neutrophil adhesion.
abstract: To reach sites of inflammation, a blood-borne neutrophil first rolls over the vessel wall, becoming firmly adherent on activation, and then transmigrates through the endothelium. In this study, we simulate the transition to firm adhesion via chemokine-induced integrin activation. To recreate the transition from rolling to firm adhesion, we use an integrated signaling adhesive dynamics simulation that includes selectin, integrin, and chemokine interactions between the cell and an adhesive substrate. Integrin bonds are of low affinity until activated by chemokine binding to G-protein coupled receptors on the model cell. The signal propagates within the cell through probabilistic diffusion and reaction of the signaling elements to induce the high-affinity integrins required for firm adhesion. This model showed that integrins become progressively active as cells roll and interact with chemokines, leading to a slight slowing before firm adhesion on a timescale similar to that observed in experiments. Increasing the density of chemokine resulted in decreases in the rolling time before stopping, consistent with experimental observations. However, a limit is reached where further increases in chemokine density do not increase adhesion. We found that the timescale for integrin activation correlated with the time to stop. Further, altering parameters within the intracellular signaling cascade that changed the speed of integrin activation, such as effector activation and dissociation rates, correspondingly affected the time to firm adhesion. For all conditions tested, the number of active integrin bonds at the point of firm adhesion was relatively constant. The model predicts that the time to stop would be relatively independent of selectin or integrin density, but strongly dependent on the shear rate because higher shear rates limit the intrinsic activation rate of integrins and require more integrins for adhesion.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Caputo
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hammer
mesh_terms: D000465:Algorithms; D002448:Cell Adhesion; D018925:Chemokines / Q000378:metabolism*; D003198:Computer Simulation; D019204:GTP-Binding Proteins / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D036904:Leukocyte Rolling; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism; D008954:Models, Biological; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000378:metabolism
chemical_list: D018925:Chemokines; D016023:Integrins; D016209:Interleukin-8; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D019007:P-Selectin; D023062:Receptors, Interleukin-8A; D018799:Intercellular Adhesion Molecule-1; D019204:GTP-Binding Proteins