Event‐Tracking Model of Adhesion Identifies Load‐Bearing Bonds in Rolling Leukocytes

Abstract

Objectives P-selectin binding to P-selectin glycoprotein ligand (PSGL)-1 mediates leukocyte rolling under conditions of inflammation and injury. The objectives were to develop an efficient, high temporal resolution model for direct simulation of leukocyte rolling, and then to conduct a study of load-bearing bonds using the model. Methods A stochastic π-calculus-driven Event Tracking Model of Adhesion was developed and compared with experimental data. Multiple simulations for each case were conducted to obtain high confidence numerical characteristics of leukocyte rolling. Results Leukocyte rolling and the underlying P-selectin—PSGL-1 bonds were studied under low wall shear rate (25-50 s-1) conditions from measured parameters of leukocyte rolling and bond properties. For the first time, the location, number, lifetime, history, and kinetics of load-bearing bonds and their influence on cell rolling are identified. Instantaneous cell displacements, translational and rotational velocities, and cell-endothelium distances are derived. The model explains the commonly observed “stop-start” type rolling behavior and reveals that a few load-bearing bonds are sufficient to support rolling while a large number of bonds dissociate before becoming load-bearing. Conclusions The presented model provides a method for precise and direct simulation of leukocyte rolling, and sets a foundation upon which further refinements can be introduced.

Dynamics of Microvillus Extension and Tether Formation in Rolling Leukocytes

“…The proposed model is in good agreement with the experimental data of Shao et al 29. Using a modified version of our Event-Tracking Model of Adhesion (ETMA)23, we conducted multiple simulations of neutrophil rolling. By directly comparing the microvillus deformation process with the lifetimes of load-bearing bonds of that microvillus, we demonstrate how P-selectin—PSGL-1 load-bearing bonds shape microvillus deformation during neutrophil rolling.…”

“…The PSGL-1 molecules are present on the microvilli tips(Figure 1). 5 Most newly created P-selectin—PSGL-1 bonds bear no load initially, and some dissociate before becoming load bearing 23. Because of the cell’s motion, bonds can become load bearing (i.e.…”

Action at a Distance: Lengthening Adhesion Bonds with Poly(ethylene glycol) Spacers Enhances Mechanically Stressed Affinity for Improved Vascular Targeting of Microparticles

“…The force dependence of HuEP-P-selectin bond lifetimes as modeled by the Bell equation38 suggested that the reactive compliance of the antibody-antigen bond, and therefore its intrinsic affinity, was unaffected by the PEG spacers and immobilization strategies. How bond length could influence bond lifetime can be explained in part by analogy to how extensible microvilli strengthen leukocyte rolling on P-selectin 26, 49, 50. In brief, the longer bond structure allows the bond to preferentially localize at the trailing edge of the moving leukocyte, or microparticle.…”

CD63 positions CD62P for rolling

“…Indeed, P-selectin Glycoprotein Ligand-1 (PSGL-1), the main leukocyte ligand for P-selectin, is a constitutive dimer, 3 and the dimers are clustered on the tips of leukocyte microvilli. 4 The rolling is insensitive to reasonable changes in the number 5 and distribution 6 of microvilli on the cell surface.…”

“…Efforts to model leukocyte rolling 5,11,12 have assumed randomly distributed P-selectin, which clearly does not capture the biologic situation on endothelial cells. Pselectin is clustered, and this clustering requires CD63.…”