Selectin catch–slip kinetics encode shear threshold adhesive behavior of rolling leukocytes

Abstract

The selectin family of leukocyte adhesion receptors is principally recognized for mediating transient rolling interactions during the inflammatory response. Recent studies using ultrasensitive force probes to characterize the force-lifetime relationship between Pand L-selectin and their endogenous ligands have underscored the ability of increasing levels of force to initially extend the lifetime of these complexes before disrupting bond integrity. This so-called ''catch-slip'' transition has provided an appealing explanation for shear threshold phenomena in which increasing levels of shear stress stabilize leukocyte rolling under flow. We recently incorporated catch-slip kinetics into a mechanical model for cell adhesion and corroborated this hypothesis for neutrophils adhering via L-selectin. Here, using adhesive dynamics simulations, we demonstrate that biomembrane force probe measurements of various Pand L-selectin catch bonds faithfully predict differences in cell adhesion patterns that have been described extensively in vitro. Using phenomenological parameters to characterize the dominant features of molecular force spectra, we construct a generalized phase map that reveals that robust shear-threshold behavior is possible only when an applied force very efficiently stabilizes the bound receptor complex. This criteria explains why only a subset of selectin catch bonds exhibit a shear threshold and leads to a quantitative relationship that may be used to predict the magnitude of the shear threshold for families of catch-slip bonds directly from their force spectra. Collectively, our results extend the conceptual framework of adhesive dynamics as a means to translate complex single-molecule biophysics to macroscopic cell behavior.force spectroscopy ͉ inflammation ͉ nanomechanics B y associating with cognate ligands on apposed surfaces, selectins expressed inducibly on the endothelial lumen (Eand P-selectin) and constitutively on the microvillar tips of peripheral blood leukocytes (L-selectin) mediate cell tethering and rolling adhesion (1). Stable rolling through L-selectin requires a threshold level of fluid shear stress, an unexpected but important consequence that prevents homotypic aggregation and inappropriate adhesion in low-shear environments (2-4). Much attention has focused on the underlying molecular kinetics to understand this behavior, with particular emphasis on the role of convective transport (5-8) and the molecular response to mechanical strain (9, 10). Several studies have now firmly established that fluid shear rate controls the tethering rate at which cells initially adhere to the substrate (6-8). Although a rate-controlled model of rolling adhesion does account for observed changes in adherent cell flux to a surface above and below the shear threshold, it does not provide a satisfactory explanation for why rolling cells in continuous contact with the surface roll progressively slower as the optimal level of fluid shear is approached. Rather, the favored hypothesis for the shear threshold po...

Adhesive Dynamics

“…We conclusively showed that the shear threshold emerges from the shifting minima in bond failure, owing to the emergence of minima with lower dissociation rates at higher shear rates, and not increasing bond formation rates at higher shear [23]. Further calculations by Beste and Hammer [6], showed when the shear threshold should emerge, and for precisely what conditions, and which molecules. For instance, a key prediction is that the conditions for which the shear threshold will emerge for P-and L-selectin are different, and these results are consistent with experiment [6].…”

“…Further calculations by Beste and Hammer [6], showed when the shear threshold should emerge, and for precisely what conditions, and which molecules. For instance, a key prediction is that the conditions for which the shear threshold will emerge for P-and L-selectin are different, and these results are consistent with experiment [6]. …”

“…We refer to c as the reactive compliance, as it sets the sensitivity of a bond to dissociation to a force; the larger the reactive compliance, the more sensitive the molecule. The Bell model only allows for cases where force accelerates dissociation, but it is now known that exceptions exist [6]. The second paper was a simple model of cell capture under shear flow that Doug Lauffenburger and I wrote, in which we could determine whether adhesion was controlled by kinetics (when the reaction rates were too slow) or by mechanics (when the reaction rates were fast) [7].…”

CD63 positions CD62P for rolling

“…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.…”

Deformation Model for Thioredoxin Catalysis of Disulfide Bond Dissociation by Force

“…An alternative definition of the catch-slip efficiency associated with the presence of both a maximum and a minimum in the force-dependent bond lifetime is given in Beste and Hammer. 5 The deformation model presented above has been successfully used to describe the anomalous dependence of the bond lifetime on the applied force in the P,L-selectins/PSGL-1 18 and actin/myosin 22 catch bonds.…”