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, 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.
Ding
Z M
ZM
Speros P. Martel Laboratory of Leukocyte Biology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Babensee
J E
JE
Simon
S I
SI
Lu
H
H
Perrard
J L
JL
Bullard
D C
DC
Dai
X Y
XY
Bromley
S K
SK
Dustin
M L
ML
Entman
M L
ML
Smith
C W
CW
Ballantyne
C M
CM
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
D018821:CD18 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha