Neutrophil elastase (NE)-deficient mice demonstrate a nonredundant role for NE in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivo.
Neutrophil elastase (NE) remains a controversial player in the process of leukocyte transmigration and much of this controversy stems from conflicting reports on the effects of NE inhibitors. The availability of NE-deficient mice (NE(-/-)) provides a clean and elegant tool for the study of leukocyte migration in vivo. In this study, NE(-/-) mice were used to investigate the role of NE in leukocyte migration through cremasteric venules, as observed by intravital microscopy, induced by locally administered cytokines IL-1beta and TNF-alpha and the particulate stimulus, zymosan. Although no defects in leukocyte responses induced by the cytokines were observed, zymosan-induced leukocyte firm adhesion and transmigration was suppressed in NE(-/-) mice. These responses were also inhibited in wild-type mice when zymosan was coinjected with a specific NE inhibitor. Quantification of inflammatory mediator levels in homogenates of zymosan-stimulated tissues indicated reductions in levels of IL-1beta, KC, and macrophage inflammatory protein-1alpha in NE(-/-) mice. Furthermore, phagocytosis of fluorescent zymosan particles, as observed by intravital microscopy, was diminished in NE-deficient animals. Collectively, the findings of this study indicate a nonredundant role for NE in zymosan-induced leukocyte firm adhesion and transmigration, and that this defect is associated with impaired generation of proinflammatory mediators as well as phagocytosis of zymosan particles in vivo.
Young
Rebecca E
RE
Cardiovascular Medicine Unit, Eric Bywaters Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, Queen Mary University of London, London, United Kingdom.
Thompson
Richard D
RD
Larbi
Karen Y
KY
La
Mylinh
M
Roberts
Clare E
CE
Shapiro
Steven D
SD
Perretti
Mauro
M
Nourshargh
Sussan
S
D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018715:Microscopy, Video; D018482:Muscle, Skeletal / Q000098:blood supply; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology*; D010529:Peritoneal Cavity / Q000166:cytology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D012611:Scrotum; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014699:Venules / Q000166:cytology / Q000276:immunology; D015054:Zymosan / Q000008:administration & dosage*
D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D019272:Leukocyte Elastase