Kinetics of β2-Integrin and L-Selectin Bonding during Neutrophil Aggregation in Shear Flow

Abstract

Activated neutrophils aggregate in a shear field via bonding of L-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) followed by a more stable bonding of LFA-1 (CD11a/CD18) to intercellular adhesion molecule 3 (ICAM-3) and Mac-1 (CD11b/CD18) to an unknown counter receptor. Assuming that the Mac-1 counter receptor is ICAM-3-like in strength and number, rate processes were deconvoluted from neutrophil homoaggregation data for shear rates (G) of 100-3000 s-1 with a two-body hydrodynamic collision model (. Biophys. J. 73:2819-2835). For integrin-mediated aggregation (characteristic bond strength of 5 microdynes) in the absence of L-selectin contributions, an average forward rate of kf = 1.57 x 10(-12) cm2/s predicted the measured efficiencies for G = 100-800 s-1. For a selectin bond formation rate constant equal to the integrin bond formation rate constant, the colloidal stability of unactivated neutrophils was satisfied for a reverse rate of the L-selectin-PGSL bond corresponding to an average bond half-life of 10 ms at a characteristic bond strength of 1 microdyne. Colliding neutrophils initially bridged by at least one L-selectin-PSGL-1 bond were calculated to rotate from 8 to 50 times at G = 400 to 3000 s-1, respectively, before obtaining mechanical stability in sheared fluid of either 0.75 or 1.75 cP viscosity. Thus for G > 400 s-1, the interaction time needed for the rotating aggregates to become stable was relatively constant at 52.5 +/- 8.5 ms, largely independent of shear rate or shear stress. Aggregation data and the colloidal stability criterion can provide a consistent set of forward and reverse rate constants and characteristic bond strengths for a known time-dependent stoichiometry of receptors on cells interacting in a shear flow field.

Multi-cell Agent-based Simulation of the Microvasculature to Study the Dynamics of Circulating Inflammatory Cell Trafficking

“…49 Previous work has predicted the effects of leukocyte deformability on adhesion kinetics, 18,39 as well as the kinetics of integrin and L-selectin mediated neutrophil aggregation under flow. 107 All of these computational models are highly detailed and mechanistically informative, but they neglect the overall spatial and temporal dynamics within entire tissues. Thus, our model fills a critical gap and provides a tool to interrogate the individual and combined effects of molecules, cell behaviors, and mechanical forces.…”

Modeling of Cell Aggregation Dynamics Governed by Receptor–Ligand Binding Under Shear Flow

“…24,52 In those pioneering work, a deterministic kinetic model was proposed, by setting a critical number of bonds to support stable formation of cell aggregates, to predict the collision efficiency and reverse rate of GPIIb/IIIa-fibrinogen binding for platelet aggregation, 45 or b 2 -integrin-ICAM-3 and L-selectin-PSGL-1 (P-selectin glycoprotein ligand 1) binding for neutrophil aggregation. 46 Recent evidence indicated that 2D receptor-ligand binding mediated by a small number of bonds is no longer a deterministic but a stochastic process. 5,7,53 To extract the molecular kinetic parameters from the time-dependent cell aggregation and disaggregation, we previously developed a probabilistic kinetic model to predict shear-induced doublet formations and breakages of red blood cells and of latex beads crossed-linked by antigen-antibody bonds.…”

Multi-scale simulation of L-selectin–PSGL-1-dependent homotypic leukocyte binding and rupture

“…Both PSGL-1 and L-selectin molecules are concentrated on tips of PMN microvilli (Puri et al 1997) (see Table 1 for their respective numbers). Homotypic PMN aggregation in vitro or in vivo is supported by multiple bonds between ( Tandon and Diamond 1998) L mv Length of microvillus 0.35 µm ( Shao et al 1998) N mv No. of microvilli/cell 252 (Chen and Springer 1999) N R No.…”