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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.
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Submitted July 11, 2008
Accepted December 22, 2008
Wound healing defect of Vav3-/- mice due to impaired  2-integrin dependent macrophage phagocytosis of apoptotic neutrophils
Anca Sindrilaru, Thorsten Peters, Jurgen Schymeinsky, Tsvetelina Oreshkova, Honglin Wang, Anne Gompf, Francesca Mannella, Meinhard Wlaschek, Cord Sunderkotter, Karl Lenhard Rudolph, Barbara Walzog, Xose R. Bustelo, Klaus D. Fischer, and Karin Scharffetter-Kochanek*
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilians University, Munich, Germany
Institute of Molecular Medicine and Max-Planck-Research Group on Stem Cell Aging, University of Ulm, Ulm, Germany
Department of Physiologic Chemistry, University of Ulm, Ulm, Germany
Department of Dermatology and Venerology, University of Munster, Munster, Germany
Centro de Investigacion del Cancer, CSIC-University of Salamanca, Salamanca, Spain
Institute of Biochemistry and Cell Biology, University of Magdeburg, Magdeburg, Germany
* Corresponding author; email: karin.scharffetter-kochanek{at}uniklinik-ulm.de.
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  2-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 co-localization with 2-integrins at the macrophage membrane upon adhesion to ICAM-1. Moreover, local injection of Vav3-/- or 2-integrin(CD18)-/- macrophages into wound margins failed to restore the healing defect of Vav3-/- mice, suggesting Vav3 to control the 2-integrin-dependent formation of a functional phagocytic synapse. Impaired phagocytosis of apoptotic neutrophils by Vav3-/- macrophages was causal for their reduced release of active TGF-1, for decreased myofibroblasts differentiation and myofibroblast-driven wound contraction. TGF-1-deficiency in Vav3-/- macrophages was causally responsible for the healing defect, as local injection of either Vav3-competent macrophages or recombinant TGF-1 into wounds of Vav3-/- mice fully rescued the delayed wound healing.
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