title: Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration.
abstract: To differentiate the unique and overlapping functions of LFA-1 and Mac-1, LFA-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-deficient 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-regulation of surface Mac-1, but did not show increased adhesion to purified ICAM-1 or endothelial cells, similar to CD18-deficient neutrophils. Adhesion of Mac-1-deficient neutrophils significantly increased with stimulation, although adhesion was lower than for wild-type neutrophils. Evaluation of the strength of adhesion through LFA-1, Mac-1, and CD18 indicated a marked reduction in firm attachment, with increasing shear stress in LFA-1-deficient neutrophils, similar to CD18-deficient neutrophils, and only a modest reduction in Mac-1-deficient neutrophils. Leukocyte influx in a subcutaneous air pouch in response to TNF-alpha was reduced by 67% and 59% in LFA-1- and CD18-deficient mice but increased by 198% in Mac-1-deficient mice. Genetic deficiencies demonstrate that both LFA-1 and Mac-1 contribute to adhesion of neutrophils to endothelial cells and ICAM-1, but adhesion through LFA-1 overshadows the contribution from Mac-1. Neutrophil extravasation in response to TNF-alpha in LFA-1-deficient mice dramatically decreased, whereas neutrophil extravasation in Mac-1-deficient mice markedly increased.
authors.affiliation: Speros P. Martel Laboratory of Leukocyte Biology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Ding
authors.forename: J E
authors.initials: JE
authors.lastname: Babensee
authors.forename: S I
authors.initials: SI
authors.lastname: Simon
authors.forename: H
authors.initials: H
authors.lastname: Lu
authors.forename: J L
authors.initials: JL
authors.lastname: Perrard
authors.forename: D C
authors.initials: DC
authors.lastname: Bullard
authors.forename: X Y
authors.initials: XY
authors.lastname: Dai
authors.forename: S K
authors.initials: SK
authors.lastname: Bromley
authors.forename: M L
authors.initials: ML
authors.lastname: Dustin
authors.forename: M L
authors.initials: ML
authors.lastname: Entman
authors.forename: C W
authors.initials: CW
authors.lastname: Smith
authors.forename: C M
authors.initials: CM
authors.lastname: Ballantyne
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002634:Chemotaxis, Leukocyte; D015194:Diffusion Chambers, Culture; D005260:Female; D007279:Injections, Subcutaneous; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018821:CD18 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha