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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4086-4095. Prepublished online as a Blood First Edition Paper on August 27, 2007August 21, 2007; DOI 10.1182/blood-2007-03-080457. This Article Full Text (PDF) Supplemental Methods and Figure All Versions of this Article: blood-2007-03-080457v1 blood-2007-03-080457v2 110/12/4086    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 Kantari, C. Articles by Witko-Sarsat, V. Search for Related Content PubMed PubMed Citation Articles by Kantari, C. Articles by Witko-Sarsat, V. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 15, 2007 Accepted August 1, 2007 Proteinase 3, the Wegener autoantigen, is externalized during neutrophil apoptosis: evidence for a functional association with phospholipid scramblase 1 and interference with macrophage phagocytosis Chahrazade Kantari, Magali Pederzoli-Ribeil, Omid Amir-Moazami, Valerie Gausson-Dorey, Yvan Cruz Moura, Marie-Chistine Lecomte, Marc Benhamou, and Veronique Witko-Sarsat* INSERM U845, Center of Research "Growth and Signaling", Universite Paris Descartes, Faculte de medecine Rene Desartes, Site Necker, Paris, France INSERMU699, Denis Diderot, "Laboratory of Renal Immunopathology and Inflammation", Universite Paris 7, Paris, France INSERM U665, Institut Francais du Sang, Paris, France * Corresponding author; email: witko-sarsat{at}necker.fr. Proteinase 3 (PR3), a serine-proteinase contained in neutrophil azurophilic granules, is considered a risk factor for vasculitides and rheumatoid arthritis, when expressed on the outer leaflet of neutrophil plasma membrane, and is the preferred target of anti-neutrophil cytoplasm autoantibodies (ANCA) in Wegener's granulomatosis. ANCA binding to PR3 on neutrophil membranes activates them. Evidence is provided that neutrophil apoptosis induced significantly more membrane PR3 expression without degranulation (but no enhanced membrane CD35, CD66b, CD63, myeloperoxidase or elastase expression). This observation was confirmed on cytoplasts, a model of granule-free neutrophils. We hypothesized that PR3 could interact with proteins involved in membrane flip-flop, e.g., phospholipid scramblase 1 (PLSCR1). PR3-PLSCR1 interaction in neutrophils was demonstrated by confocal microscopy and co-immunoprecipitation. In the RBL-2H3 rat mast-cell line stably transfected with PR3 or its inactive mutant (PR3S203A), PR3 externalization depended on PLSCR1, as shown by less PR3 externalization in the presence of rPLSCR1-siRNA, but independently of its serine-proteinase activity. Finally, apoptosis-externalized PR3 decreased the human macrophage-phagocytosis rate of apoptotic PR3 transfectants. Therefore, in addition to ANCA-binding in vasculitis, the pro-inflammatory role of membrane PR3 expression may involve interference with macrophage clearance of apoptotic neutrophils. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Jensen, L. Andresen, K. A. Hansen, and S. Skov Cell-surface expression of Hsp70 on hematopoietic cancer cells after inhibition of HDAC activity J. Leukoc. Biol., October 1, 2009; 86(4): 923 - 932. [Abstract] [Full Text] [PDF] B. Korkmaz, J. Jaillet, M.-L. Jourdan, A. Gauthier, F. Gauthier, and S. 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