Wound healing defect of Vav3-/- mice due to impaired {beta}2-integrin-dependent macrophage phagocytosis of apoptotic neutrophils.
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 beta(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 colocalization with beta(2)-integrins at the macrophage membrane upon adhesion to ICAM-1. Moreover, local injection of Vav3(-/-) or beta(2)-integrin(CD18)(-/-) macrophages into wound margins failed to restore the healing defect of Vav3(-/-) mice, suggesting Vav3 to control the beta(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 transforming growth factor (TGF)-beta(1), for decreased myofibroblasts differentiation and myofibroblast-driven wound contraction. TGF-beta(1) deficiency in Vav3(-/-) macrophages was causally responsible for the healing defect, as local injection of either Vav3-competent macrophages or recombinant TGF-beta(1) into wounds of Vav3(-/-) mice fully rescued the delayed wound healing.
Sindrilaru
Anca
A
Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
Peters
Thorsten
T
Schymeinsky
Jürgen
J
Oreshkova
Tsvetelina
T
Wang
Honglin
H
Gompf
Anne
A
Mannella
Francesca
F
Wlaschek
Meinhard
M
Sunderkötter
Cord
C
Rudolph
Karl Lenhard
KL
Walzog
Barbara
B
Bustelo
Xosé R
XR
Fischer
Klaus D
KD
Scharffetter-Kochanek
Karin
K
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018821:CD18 Antigens / Q000276:immunology*; D007962:Leukocytes; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014945:Wound Healing / Q000276:immunology*
D018821:CD18 Antigens; D051567:Proto-Oncogene Proteins c-vav; D016212:Transforming Growth Factor beta; C496622:Vav3 protein, mouse