Synergistic Regulation Mechanism of Selectin and Integrin on Leukocyte Adhesion Under Shear Flow

Abstract

In the process of inflammation, the hydrodynamic process of circulating leukocyte recruitment to the inflammatory site requires the rolling adhesion of leukocytes in blood vessels mediated by selectin and integrin molecules. Although a number of experiments have demonstrated that cooperative effects exist between selectins and integrins in leukocyte rolling adhesion under shear flow, the mechanisms underlying how the mechanics of selectins and integrins synergistically may govern the dynamics of cell rolling is not yet fully resolved. Here we present a mechanical model on selectin- and integrin- jointly mediated rolling adhesion of leukocyte in shear flow, by considering two pairs' binding/unbinding events as Markov processes and describing kinetics of leukocyte by the approach of continuum mechanics. Through examining the dynamics of leukocyte rolling as a function of relative fraction of selectin and integrin pairs, we show that, during recruitment, the elongation of intermittent weak selectin bonds consuming the kinetic energy of rolling leukocyte decelerates the rolling speed and enables the integrin pairs to form strong bonds, therefore achieving the arrestment of leukocyte (firm adhesion). The coexistence of selectins and integrins may also be required for effective phase transition from firm adhesion to rolling adhesion, due to dynamic competition in pairs' formation and elongation. These results are verified by the relevant Monte Carlo simulations and related to reported experimental observations.

Stochastic dynamics of substrate non-uniform stiffness affecting molecular adhesion in cell–substrate interface subjected to tensile loading

“…Specifically, during cell rolling adhesion under hydrodynamic stimulate from shear flow, owing to the different pathways of adhesive traction during detaching and approaching processes of two surfaces, the adhesion hysteresis of contacting surfaces leading to energy dissipation can significantly regulate the kinetics of rolling adhesion of cell. 36,37 However, because a large fluctuation towards the absorbing boundary inevitably leads to a runaway process, it is difficult to directly obtain the approaching process of two contacting surfaces from the current Monte Carlo simulations. Moreover, since we currently focused on tensile fatigue of the adhesive interface, regarding the non-uniform elastic substrate, the adhesion hysteresis induced by the different pathways of adhesive traction during two surfaces advancing and receding is worthy of future investigation.…”

“…Essentially, during cell-substrate interaction, the molecular bond forming and breaking are highly stochastic and reversible processes. Referring to these characteristics of molecular bonds, extensive efforts have been conducted to address dynamics of molecular bond clusters [20][21][22][23] and their response to external mechanical stimulus, such as dynamic loading, [24][25][26][27] substrate elasticity or viscosity, [28][29][30][31] substrate surface morphology, 32 membrane fluctuations, 33,34 hydrodynamic impact from the blood flow [35][36][37][38] and membrane surface tension. 39 Nevertheless, these attentions are mainly focused This is the author's peer reviewed, accepted manuscript.…”