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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 Vivo¹

Rebecca E. Young^*, Richard D. Thompson^*, Karen Y. Larbi^*, Mylinh La, Clare E. Roberts^*, Steven D. Shapiro, Mauro Perretti and Sussan Nourshargh^2,*

^* Cardiovascular Medicine Unit, Eric Bywaters Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, and William Harvey Research Institute, Bart’s and the London, Queen Mary University of London, London, United Kingdom; and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

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-1 and TNF- 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-1, KC, and macrophage inflammatory protein-1 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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