Abstract
Leukocyte recruitment from the bloodstream to surrounding tissues is an essential component of the immune response. Capture of blood-borne leukocytes onto vascular endothelium proceeds via a two-step mechanism, with each step mediated by a distinct receptor-ligand pair. Cells first transiently adhere, or "roll" (via interactions between selectins and sialyl-Lewis-x), and then firmly adhere to the vascular wall (via interactions between integrins and ICAM-1). We have reported that a computational method called adhesive dynamics (AD) accurately reproduces the fine-scale dynamics of selectin-mediated rolling. This paper extends the use of AD simulations to model the dynamics of cell adhesion when two classes of receptors are simultaneously active: one class (selectins or selectin ligands) with weakly adhesive properties, and the other (integrins) with strongly adhesive properties. AD simulations predict synergistic functions of the two receptors in mediating adhesion. At a fixed density of surface ICAM-1, increasing selectin densities lead to greater pause times and an increased tendency toward firm adhesion; thus, selectins mechanistically facilitate firm adhesion mediated by integrins. Conversely, at a fixed density of surface selectin, increasing ICAM-1 densities lead to greater pause times and an increased tendency to firm adhesion. We present this relationship in a two-receptor state diagram, a map that relates the densities and properties of adhesion molecules to various adhesive behaviors that they code, such as rolling or firm adhesion. We also present a state diagram for neutrophil activation, which relates beta(2)-integrin density and integrin-ICAM-1 kinetic on rate to neutrophil adhesive behavior. The predictions of two-receptor adhesive dynamics are validated by the ability of the model to reproduce in vivo neutrophil rolling velocities from the literature.