Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration

To differentiate the unique and overlapping functions of LFA-1 and Mac-1, L PA-1-deficient mice were developed by targeted homologous recombination in embryonic stem cells, and neutrophil function was compared in vitro and in vivo with Mac-1-deficient, CD18-deficient, and wild-type mice. LFA-1-defici ent mice exhibit leukocytosis but do not develop spontaneous infections, in contrast to CD18-deficient mice. After zymosan-activated serum stimulation , LFA-1-deficient neutrophils demonstrated activation, evidenced by up-regu lation of surface Mac-1, but did not show increased adhesion to purified IC AM-1 or endothelial Cells, similar to CD18-deficient neutrophils, Adhesion of Mac-1-deficient neutrophils significantly increased with stimulation, al though adhesion was lower than for wild-type neutrophils. Evaluation of the strength of adhesion through LFA-1, Mac-1, and CD18 indicated a marked red uction in firm attachment, with increasing shear stress in LFA-1-deficient neutrophils. Similar to CD18-deficient neutrophils, and only a modest reduc tion in Mac-1-deficient neutrophils. Leukocyte influx in::a subcutaneous ai r pouch in response to TNF-alpha was reduced by 67% and 59% in LFA-1- and C D18-deficient mice but increased by 198% in Mac-1-deficient mice. Genetic d eficiencies demonstrate that both LFA-1 and Mac-1 contribute to adhesion of ;neutrophils to endothelial cells and ICAM-1, but adhesion through LFA-1 ov ershadows the contribution from Mac-1, Neutrophil extravasation in response to TNF-alpha in LFA-1-deficient mice dramatically decreased, whereas neutr ophil extravasation in Mac-1-deficient mice markedly increased.