Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts - role of TGFβ1 levels and RhoA activity.
Wound healing crucially relies on the mechanical activity of fibroblasts responding to TGFβ1 and to forces transmitted across focal adhesions. Integrin-linked kinase (ILK) is a central adapter recruited to integrin β1 tails in focal adhesions mediating the communication between cells and extracellular matrix. Here, we show that fibroblast-restricted inactivation of ILK in mice leads to impaired healing due to a severe reduction in the number of myofibroblasts, whereas inflammatory infiltrate and vascularization of the granulation tissue are unaffected. Primary ILK-deficient fibroblasts exhibit severely reduced levels of extracellular TGFβ1, α-smooth muscle actin (αSMA) production and myofibroblast conversion, which are rescued by exogenous TGFβ1. They are further characterized by elevated RhoA and low Rac1 activities, resulting in abnormal shape and reduced directional migration. Interference with RhoA-ROCK signaling largely restores morphology, migration and TGFβ1 levels. We conclude that, in fibroblasts, ILK is crucial for limiting RhoA activity, thus promoting TGFβ1 production, which is essential for dermal repair following injury.
Blumbach
Katrin
K
Department of Dermatology, University of Cologne, Kerpener Strasse. 62, D-50937 Cologne, Germany.
Zweers
Manon C
MC
Brunner
Georg
G
Peters
Andreas S
AS
Schmitz
Markus
M
Schulz
Jan-Niklas
JN
Schild
Alexander
A
Denton
Christopher P
CP
Sakai
Takao
T
Fässler
Reinhard
R
Krieg
Thomas
T
Eckes
Beate
B
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D006097:Granulation Tissue / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099200:Scaffold Protein ILK
D000199:Actins; D017346:Protein Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; D020830:rac1 GTP-Binding Protein; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000099200:Scaffold Protein ILK; C544013:alpha-smooth muscle actin, mouse