A 3-D Computational Model Predicts that Cell Deformation Affects Selectin-Mediated Leukocyte Rolling

Abstract

Leukocyte recruitment to sites of inflammation is initiated by their tethering and rolling on the activated endothelium under flow. Even though the fast kinetics and high tensile strength of selectin-ligand bonds are primarily responsible for leukocyte rolling, experimental evidence suggests that cellular properties such as cell deformability and microvillus elasticity actively modulate leukocyte rolling behavior. Previous theoretical models either assumed cells as rigid spheres or were limited to two-dimensional representations of deformable cells with deterministic receptor-ligand kinetics, thereby failing to accurately predict leukocyte rolling. We therefore developed a three-dimensional computational model based on the immersed boundary method to predict receptor-mediated rolling of deformable cells in shear flow coupled to a Monte Carlo method simulating the stochastic receptor-ligand interactions. Our model predicts for the first time that the rolling of more compliant cells is relatively smoother and slower compared to cells with stiffer membranes, due to increased cell-substrate contact area. At the molecular level, we show that the average number of bonds per cell as well as per single microvillus decreases with increasing membrane stiffness. Moreover, the average bond lifetime decreases with increasing shear rate and with increasing membrane stiffness, due to higher hydrodynamic force experienced by the cell. Taken together, our model captures the effect of cellular properties on the coupling between hydrodynamic and receptor-ligand bond forces, and successfully explains the stable leukocyte rolling at a wide range of shear rates over that of rigid microspheres.