Mechanism of force-induced activation of integrin LFA-1 under circulating flows / 医用生物力学

ABSTRACT

Objective To reveal the mechanical regulation mechanism for activation of lymphocyte function-associated antigen 1 (LFA-1). Methods The LFA-1 expressed on Jurkat cell surface was pre-activated by Mg2+ from quiescent-to intermediate-affinity state, and the tether events of Jurkat cells under different wall shear stresses (4.5-10 mPa) were observed and analyzed by flow chamber experiment. Meanwhile, a probabilistic model of integrin affinity jumping was established. Results The affinity jumping model was well fitted with the data obtained from flow chamber experiment. Under flowing loads, LFA-1 from intermediate to high-affinity state was observed, with prolonging of the adhesion bonds. The probability of tether event was 15%-26%. LFA-1 at high-affinity state contributed a significant fraction (about 26%-40%) of the bond lifetime. The off-rate of LFA-1 at high-affinity state was slower by 19%-65% as compared to that at intermediate-affinity state. Dissociating of ICAM-1 from LFA-1 was force-dependent and governed either by slip-bond at intermediate-affinity state or by catch-slip bond at high-affinity state. Conclusions The force-induced activation of LFA-1 mediates the slower rolling and firm adhesion of the cells. This research finding will further the understanding of inflammatory response events of circulating leukocytes, and contribute to the discovery of new antibody drug targets for the associated diseases.