Integrin subtype-dependent CD18 cleavage under shear and its influence on leukocyte-platelet binding.

Previous studies showed that exposure of neutrophils to shear stress induces cysteine protease-mediated shedding of surface CD18 integrins involved in leukocyte-platelet interactions. Based on this, we hypothesized that, under noninflamed conditions, shear-induced CD18 cleavage is a control mechanism to minimize spontaneous leukocyte-platelet binding. For this purpose, we characterized the influence of shear on CD18 surface expression and platelet binding by the different leukocyte subsets. Shear stress elicited magnitude- (between 0 and 5 dyn/cm(2)) and time-dependent reductions in CD18 surface expression. This response was integrin- and cell type-specific, with neutrophils and monocytes exhibiting Mac-1 proteolysis but lymphocytes displaying LFA-1 shedding. Correspondingly, platelet binding, through CD18-fibrinogen interactions, was also influenced by shear exposure in a leukocyte-dependent manner. After treatment with cysteine protease inhibitor E64, neutrophils, but neither monocytes nor lymphocytes, exhibited significantly (P<0.05) enhanced platelet binding and CD18 surface expression under shear. Furthermore, shear exposure significantly (P<0.05) inhibited binding of naïve but not E64-treated neutrophils to fibrinogen. Combined, we provide first evidence that the CD18-cleavage responses of neutrophils to shear interfere with fibrinogen binding and platelet adhesion. These findings have implications as it relates to the efficiency of leukocyte passage through the microcirculation.