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Blood, 21 May 2009, Vol. 113, No. 21, pp. 5266-5276. Prepublished online as a Blood First Edition Paper on January 15, 2009; DOI 10.1182/blood-2008-07-166702. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-07-166702v1 113/21/5266    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 Sindrilaru, A. Articles by Scharffetter-Kochanek, K. Search for Related Content PubMed PubMed Citation Articles by Sindrilaru, A. Articles by Scharffetter-Kochanek, K. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Wound healing defect of Vav3–/– mice due to impaired β2-integrin–dependent macrophage phagocytosis of apoptotic neutrophils Anca Sindrilaru1,*, Thorsten Peters1,*, Jürgen Schymeinsky2, Tsvetelina Oreshkova1, Honglin Wang1, Anne Gompf3, Francesca Mannella4, Meinhard Wlaschek1, Cord Sunderkötter5, Karl Lenhard Rudolph3, Barbara Walzog2, Xosé R. Bustelo6, Klaus D. Fischer4,7, and Karin Scharffetter-Kochanek1 1 Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany; 2 Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilians University, Munich, Germany; 3 Institute of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging and 4 Department of Physiologic Chemistry, University of Ulm, Ulm, Germany; 5 Department of Dermatology and Venerology, University of Münster, Münster, Germany; 6 Centro de Investigación del Cáncer, CSIC–University of Salamanca, Salamanca, Spain; and 7 Institute of Biochemistry and Cell Biology, University of Magdeburg, Magdeburg, Germany Vav proteins are guanine-nucleotide exchange factors implicated in leukocyte functions by relaying signals from immune response receptors and integrins to Rho-GTPases. We here provide first evidence for a role of Vav3 for β2-integrins–mediated macrophage functions during wound healing. Vav3–/– and Vav1–/–/Vav3–/– mice revealed significantly delayed healing of full-thickness excisional wounds. Furthermore, Vav3–/– bone marrow chimeras showed an identical healing defect, suggesting that Vav3 deficiency in leukocytes, but not in other cells, is causal for the impaired wound healing. Vav3 was required for the phagocytotic cup formation preceding macrophage phagocytosis of apoptotic neutrophils. Immunoprecipitation and confocal microscopy revealed Vav3 activation and colocalization with β2-integrins at the macrophage membrane upon adhesion to ICAM-1. Moreover, local injection of Vav3–/– or β2-integrin(CD18)–/– macrophages into wound margins failed to restore the healing defect of Vav3–/– mice, suggesting Vav3 to control the β2-integrin–dependent formation of a functional phagocytic synapse. Impaired phagocytosis of apoptotic neutrophils by Vav3–/– macrophages was causal for their reduced release of active transforming growth factor (TGF)-β1, for decreased myofibroblasts differentiation and myofibroblast-driven wound contraction. TGF-β1 deficiency in Vav3–/– macrophages was causally responsible for the healing defect, as local injection of either Vav3-competent macrophages or recombinant TGF-β1 into wounds of Vav3–/– mice fully rescued the delayed wound healing. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Regeneration after death: Vav3 to the rescue Veera D'mello and Raymond B. Birge Blood 2009 113: 5037-5038. [Full Text] [PDF] microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification Basile Stamatopoulos, Nathalie Meuleman, Benjamin Haibe-Kains, Pascale Saussoy, Eric Van Den Neste, Lucienne Michaux, Pierre Heimann, Philippe Martiat, Dominique Bron, and Laurence Lagneaux Blood 2009 113: 5237-5245. [Abstract] [Full Text] [PDF] This article has been cited by other articles: V. D'mello and R. B. Birge Regeneration after death: Vav3 to the rescue Blood, May 21, 2009; 113(21): 5037 - 5038. [Full Text] [PDF]

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