Immune complex-stimulated neutrophil LTB4 production is dependent on β2 integrins

Abstract

The β2 integrins (LFA-1, Mac-1, and p150,95) are critical for many adhesive functions of leukocytes. Although the binding of the IgG-opsonized particles occurs normally in the absence of β2 integrins, phagocytosis of IgG-opsonized particles by activated neutrophils (PMN) requires these integrins. This observation suggests a role for β2 integrins in phagocytosis subsequent to particle binding. To investigate the mechanism of involvement of ft integrins in IgG-mediated functions, we examined the role of ft integrins in adhesion to immune complex (IC)-coated surfaces. Initial adhesion and spreading on IC-coated surfaces were equivalent in control and β2-deficient phagocytes. However, both genetically β2-deficient PMN and PMN treated with the anti-β2 mAb IB4 subsequently detached from the IC-coated surfaces. To determine whether biochemical consequences of IgG activation were also affected by ft deficiency, LTB4 production in response to Fc receptor ligation was assessed. LTB4 production by β2-deficient PMN adherent to IC-coated surfaces was markedly decreased in comparison with control PMN. Importantly. LTB4 production by PMN stimulated with fluid phase heataggregated IgG also required the β2 integrins, showing that the defect was not a simple consequence of abnormal adhesion. In contrast, Superoxide production by IC-adherent PMN was equivalent in control and β2-deficient PMN. The initial rises in intracytoplasmic [Ca2+]i in response to aggregated IgG also were unaffected by inhibition of β2 integrins. These data show that lack of β2 integrins does not inhibit all FcR-dependent signal transduction. Finally, LTB4 production by normal PMN adherent to ICs was inhibited by antibodies to FcRII, but not FcRIII, showing that FcRII ligation was required for this effect. Together these data identify a role for the β2 integrins in a signal transduction pathway leading to sustained adhesion and LTB4 production in response to IC. Since both β2 integrins and FcRII are required for these effects, the data further suggest cooperation between these receptors in generating PMN activation in response to IC stimulation.