Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.
We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18(-/-) mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers alpha-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18(-/-) mice, suggesting an impaired myofibroblast differentiation. TGF-beta signalling was clearly involved since TGF-beta1 and TGF-beta receptor type-II protein levels were decreased, while TGF-beta(1) injections into wound margins fully re-established wound closure. Since, in CD18(-/-) mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18(-/-) neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-beta1. Indeed, in neutrophil-macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-beta1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing.
Peters
Thorsten
T
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Sindrilaru
Anca
A
Hinz
Boris
B
Hinrichs
Ralf
R
Menke
André
A
Al-Azzeh
Ezz Al Din
EA
Holzwarth
Katrin
K
Oreshkova
Tsvetelina
T
Wang
Honglin
H
Kess
Daniel
D
Walzog
Barbara
B
Sulyok
Silke
S
Sunderkötter
Cord
C
Friedrich
Wilhelm
W
Wlaschek
Meinhard
M
Krieg
Thomas
T
Scharffetter-Kochanek
Karin
K
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D018821:CD18 Antigens / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D007150:Immunohistochemistry; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
D000199:Actins; D018821:CD18 Antigens; D016207:Cytokines; D005353:Fibronectins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1