Adhesive dynamics simulations of the mechanical shedding of L-selectin from the neutrophil surface.

Here we accurately recreate the mechanical shedding of L-selectin and its effect on the rolling behavior of neutrophils in vitro using the adhesive dynamics simulation by incorporating the shear-dependent shedding of L-selectin. We have previously shown that constitutively expressed L-selectin is cleaved from the neutrophil surface during rolling on a sialyl Lewis x-coated planar surface at physiological shear rates without the addition of exogenous stimuli. Utilizing a Bell-like model to describe a shedding rate which presumably increases exponentially with force, we were able to reconstruct the characteristics of L-selectin-mediated neutrophil rolling observed in the experiments.

Adhesive dynamics simulation of G-protein-mediated chemokine-activated neutrophil adhesion.

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.

Adhesive dynamics simulation of neutrophil arrest with stochastic activation.

The transition from rolling to firm adhesion is a key step in the adhesion cascade that permits a neutrophil to exit the bloodstream and make its way to a site of inflammation. In this work, we construct an integrated model of neutrophil activation and arrest that combines a biomechanical model of neutrophil adhesion and adhesive dynamics, with fully stochastic signal transduction modeling, in the form of kinetic Monte Carlo simulation within the microvilli. We employ molecular binding parameters gleaned from the literature and from simulation of cell-free rolling mediated by selectin molecules.

Adhesive dynamics simulations of the shear threshold effect for leukocytes.

Many experiments have measured the effect of force on the dissociation of single selectin bonds, but it is not yet clear how the force dependence of molecular dissociation can influence the rolling of cells expressing selectin molecules. Recent experiments using constant-force atomic force microscopy or high-resolution microscopic observations of pause-time distributions of cells in a flow chamber show that for some bonds, the dissociation rate is high at low force and initially decreases with force, indicating a catch bond. As the force continues to increase, the dissociation rate increases again, like a slip bond.

Effect of microvillus deformability on leukocyte adhesion explored using adhesive dynamics simulations.

Leukocyte rolling on the endothelium via selectin molecules is an important step in the adhesion cascade, which allows leukocytes in the bloodstream to reach sites of infection. We improve upon Adhesive Dynamics simulations by incorporating deformable microvilli on which adhesion molecules are clustered. As determined in micropipette experiments, microvilli deform like an elastic spring at small forces and a combination of yield and viscous dissipation at high forces.