The Mechanical Regulation Mechanism Of Integrin Activation Under Chemokine Treatment

In inflammation process, before rolling leukocytes emigrate into tissue, firm arrest mediated by integrin is needed. As interaction between the integrin and its ligand is important in this process, it is significant to investigate the mechanism of integrin activation. Although results of molecular dynamic simulation already proved that force can influence the activation of integrin, no evidences were found in physiological experiment. Thus we use flow chamber to provide a physiological environment to study how forces influence integrin activation.Integrin presents in three affinity states: low, intermediate and high affinity. In flow chamber experiment, we first used chemokine CXCL12 to activate integrin to intermediate affinity, and then we observed how shear stresses activated intermediate integrin to high affinity. Without chemokine, low affinity integrin could not adhere to substrates that coated with ICAM-1. We found that as the shear stress increased, the off rate of integrin decreased and then increased, represented “catch bond” and “slip bond”, respectively. We built an integrin transition model to describe the process of integrin transition between intermediate affinity and high affinity. In low shear stress, only low affinity integrin was found. As shear stress increased to the optimum, integrin transfer from intermediate affinity to high affinity immediately. However, when shear stress increased continually, longer time was needed for integrin to transfer from intermediate affinity to high affinity.The findings of how force influence integrin activation would be hoped to supply useful information and new ideas for the new drug designing.