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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, 2007; DOI 10.1182/blood-2007-03-080457. This Article Full Text 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 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 Kantari, C. Articles by Witko-Sarsat, V. Search for Related Content PubMed PubMed Citation Articles by Kantari, C. Articles by Witko-Sarsat, V. Related Collections Phagocytes Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES 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 Kantari1, Magali Pederzoli-Ribeil1, Omid Amir-Moazami2, Valérie Gausson-Dorey1, Ivan Cruz Moura2, Marie-Christine Lecomte3, Marc Benhamou2, and Véronique Witko-Sarsat1 1 Institut National de la Santé et de la Recherche Médicale (INSERM), U845, Paris, and Université Paris Descartes, Faculté de Médecine René Descartes, Site Necker, Center of Research Growth and Signaling, Paris; 2 INSERM, U699, Paris, Université Paris 7- Denis Diderot, Laboratory of Renal Immunopathology and Inflammation, Paris; and 3 INSERM, U665, Paris, Institut Français du Sang, Paris, France 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 antineutrophil cytoplasm autoantibodies (ANCA) in Wegener granulomatosis. ANCA binding to PR3 expressed at the surface of neutrophils 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 (eg, phospholipid scramblase 1 [PLSCR1]). PR3-PLSCR1 interaction in neutrophils was demonstrated by confocal microscopy and coimmunoprecipitation. 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 proinflammatory 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: A. Mueller, K. Holl-Ulrich, P. Lamprecht, and W. L. Gross Germinal centre-like structures in Wegener's granuloma: the morphological basis for autoimmunity? Rheumatology, August 1, 2008; 47(8): 1111 - 1113. [Full Text] [PDF] D. Smrz, P. Lebduska, L. Draberova, J. Korb, and P. Draber Engagement of Phospholipid Scramblase 1 in Activated Cells: IMPLICATION FOR PHOSPHATIDYLSERINE EXTERNALIZATION AND EXOCYTOSIS J. Biol. Chem., April 18, 2008; 283(16): 10904 - 10918. [Abstract] [Full Text] [PDF]

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