Leukocytes homing to peripheral sites of immune challenge rely on rapid activation of ‘inside-out' signaling pathways to trigger localized cell arrest and emigration into surrounding tissues. This cascade is initiated by endothelial-displayed chemokines which bind G-protein coupled receptors at the cell interface and culminates in the activation of resting surface integrins. Using a computational approach to model biochemical transduction events, we address how the intracellular organization of such ‘inside-out' signaling networks impacts the efficiency of cell arrest. In particular, we focus on the regulation of the β₂ integrin, LFA-1, whose affinity is modulated by the small GTPase Rap1. Our stochastic framework explicitly simulates the temporal and spatial evolution of known molecular species downstream of the chemokine receptor leading to Rap1 and subsequent LFA-1 activation. The dynamics of integrin activation are synchronized to Adhesive Dynamics simulations which model the mechanics of adhesion and predict the overall likelihood for cell arrest.

Using this integrated modeling strategy, we demonstrate how feedback and amplification motifs within the signaling pathway confer leukocytes with a tunable sensitivity to chemotactic stimuli. These predictions are consistent with experimental measurements recently obtained from combined signaling and adhesion assays on human neutrophils. We extrapolate our general findings to consider the specialized case of lymphocytes which activate integrins through multiple chemokine receptors. When downstream signals cross-regulate two or more receptors, the model predicts that the ‘inside-out' network can elicit functional synergy in the adhesion response and trigger cell arrest at sub-optimal levels of chemokine exposure.