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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2557-2564. Prepublished online as a Blood First Edition Paper on July 13, 2004; DOI 10.1182/blood-2004-01-0191. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-01-0191v1 2004-01-0191v2 104/8/2557    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Scheel-Toellner, D. Articles by Lord, J. M. Search for Related Content PubMed PubMed Citation Articles by Scheel-Toellner, D. Articles by Lord, J. M. Related Collections Phagocytes Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES Reactive oxygen species limit neutrophil life span by activating death receptor signaling Dagmar Scheel-Toellner, Keqing Wang, Rachel Craddock, Paul R. Webb, Helen M. McGettrick, Lakhvir Kaur Assi, Neal Parkes, Louise E. Clough, Erich Gulbins, Mike Salmon, and Janet M. Lord From the Medical Research Council (MRC) Centre for Immune Regulation, Division of Immunity and Infection, University of Birmingham, United Kingdom; and the Department of Molecular Biology, University of Essen, Germany.. Neutrophils are abundant, short-lived leukocytes, and their death by apoptosis is central to hemostasis and the resolution of inflammation, yet the trigger for their entry into apoptosis is unknown. We show here that death receptor signaling, including CD95 death-inducing signaling complex (DISC) formation and caspase 8 activation, occurred early in neutrophil apoptosis. However, death receptor ligation was not required for apoptosis, suggesting a novel mechanism for caspase 8 activation. We detected ceramide generation and clustering of CD95 in lipid rafts early in neutrophil apoptosis, and neutrophil apoptosis and ceramide generation were both significantly inhibited in acid sphingomyelinase knockout (ASM–/–) mice compared to wild-type littermates. Further studies revealed that ceramide generation, CD95 clustering, and neutrophil apoptosis were dependent on reactive oxygen species (ROSs) and were preceded by a fall in reduced glutathione levels. We propose that accumulation of ROSs, as a consequence of altered redox status, initiates ligand-independent death receptor signaling via activation of ASM and clustering of preformed DISC components in lipid rafts and is therefore a primary factor limiting neutrophil life span. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. H. Wong, N. Francis, H. Chahal, K. Raza, M. Salmon, D. Scheel-Toellner, and J. M. Lord Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluid Rheumatology, January 1, 2009; 48(1): 39 - 44. [Abstract] [Full Text] [PDF] A. M. Giammarioli, A. Maselli, A. Casagrande, L. Gambardella, A. Gallina, M. Spada, A. Giovannetti, E. Proietti, W. Malorni, and M. Pierdominici Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism Cancer Res., July 1, 2008; 68(13): 5291 - 5300. [Abstract] [Full Text] [PDF] A. Brozovic, D. 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