Dynamic simulations of inflammatory cell recruitment: the state diagram for cell adhesion mediated by two receptors

White blood cell 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) with weakly adhesive properties, and the other (integrins) with strongly adhesive properties. AD simulations predict synergistic functions of the two receptors in mediating 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. The predictions of two-receptor adhesive dynamics are validated by the ability of the model to reproduce experimental neutrophil rolling velocities.