Signaling mechanism for equine neutrophil activation by immune complexes

Neutrophils (PMN) are critical host defense cells that have a role in the p athophysiology of a variety of inflammatory diseases, particularly those di seases associated with antigen-antibody immune complexes (IC) deposited in tissues. Activation of PMN by IC is most efficient if the IC are presented immobilized on a surface. Adhesion to the immobilized IC is important for s ubsequent activation of PMN effector functions, such as generation of react ive oxygen metabolites. Adhesion of human PMN to immobilized IC requires th e expression and activation of adhesion receptors called integrins. Of the integrins expressed on PMN, the beta 2 family has been found to be of parti cular importance for PMN function. The mechanism of beta 2 integrin activat ion during adhesion to IC has been studied in human PMN, but not in equine PMN. We show here that adhesion of equine PMN to immobilized IC requires be ta 2 integrins. Like adhesion, IC-induced respiratory burst activity is dep endent on beta 2 integrins. Furthermore, the signaling pathway triggering b eta 2 integrin-dependent adhesion of equine PMN to IC and subsequent genera tion of respiratory burst activity is inhibited by the specific phosphatidy linositol 3-kinase (PI3K) antagonists wortmannin and LY294002 with IC50 (co ncentration at which 50% inhibition is achieved) similar to the published v alues for inhibition of PI3K enzymatic activity. In contrast, PMA-induced a ctivation of beta 2 integrin-dependent adhesion and respiratory burst activ ity are wortmannin and LY294002 insensitive. These data demonstrate that li ke in human PMN, IC-induced activation of beta 2 integrins and beta 2 integ rin-dependent functions in equine PMN is dependent on PI3K activity. (C) 20 01 Elsevier Science B.V. All rights reserved.