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PMID:15034066

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Citation

Young, RE, Thompson, RD, Larbi, KY, La, M, Roberts, CE, Shapiro, SD, Perretti, M and Nourshargh, S (2004) 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. J. Immunol. 172:4493-502

Abstract

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.

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Keywords

Animals; Cell Adhesion Molecules/biosynthesis; Inflammation Mediators/antagonists & inhibitors; Inflammation Mediators/metabolism; Interleukin-1/pharmacology; Leukocyte Elastase/deficiency; Leukocyte Elastase/genetics; Leukocyte Elastase/physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Video; Muscle, Skeletal/blood supply; Neutrophil Infiltration/genetics; Neutrophil Infiltration/immunology; Neutrophils/enzymology; Neutrophils/immunology; Peritoneal Cavity/cytology; Phagocytosis/genetics; Phagocytosis/immunology; Scrotum; Tumor Necrosis Factor-alpha/pharmacology; Venules/cytology; Venules/immunology; Zymosan/administration & dosage

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