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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, 2004July 6, 2004; DOI 10.1182/blood-2004-01-0191. This Article 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 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 Lord, J. M Articles by Salmon, M. Search for Related Content PubMed PubMed Citation Articles by Lord, J. M Articles by Salmon, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 16, 2004 Accepted June 14, 2004 Reactive Oxygen Species limit Neutrophil lifespan by activating Death Receptor Signaling Janet M Lord*, Dagmar Scheel-Toellner, Keqing Wang, Rachel Craddock, Paul R Webb, Helen M McGettrick, Lakhvir K Assi, Neal Parkes, Louise E Clough, Erich Gulbins, and Mike Salmon Division of Immunity and Infection, MRC Centre for Immune Regulation, University of Birmingham, Birmingham, West Midlands, United Kingdom Department of Molecular Biology, University of Essen, Essen, Germany * Corresponding author; email: J.M.Lord{at}bham.ac.uk. Neutrophils are abundant, short-lived leucocytes and their death by apoptosis is central to haemostasis and the resolution of inflammation, yet the trigger for their entry into apoptosis is unknown. We show here that death receptor signalling, including CD95 Death Inducing Signalling 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 (ROS) and were preceded by a fall in reduced glutathione levels. We propose that accumulation of ROS, as a consequence of altered redox status, initiates ligand-independent death receptor signalling via activation of ASM and clustering of pre-formed DISC components in lipid rafts and is therefore a primary factor limiting neutrophil lifespan. 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] S. Uhlig and E. Gulbins Sphingolipids in the Lungs Am. J. Respir. Crit. Care Med., December 1, 2008; 178(11): 1100 - 1114. [Abstract] [Full Text] [PDF] Y. Zhang, X. Li, A. Carpinteiro, and E. Gulbins Acid Sphingomyelinase Amplifies Redox Signaling in Pseudomonas aeruginosa-Induced Macrophage Apoptosis J. 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