TAK1 Is Required for Dermal Wound Healing and Homeostasis

• Published in: Journal of investigative dermatology Vol. 133; no. 6; pp. 1646 - 1654
• Main Authors: Guo, Fen, Hutchenreuther, James, Carter, David E., Leask, Andrew
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2013; Elsevier Limited
• Subjects: Animals; Cell Adhesion - physiology; Cell Movement - physiology; Cell Proliferation; Cells, Cultured; Dermis - cytology; Dermis - physiology; Fibroblasts - cytology; Fibroblasts - physiology; Homeostasis - physiology; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - physiology; Mice; Mice, Knockout; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - pharmacology; Wound Healing - physiology; Zearalenone - analogs & derivatives; Zearalenone - pharmacology
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2013.28

Dermal connective tissue is a supportive structure required for skin’s barrier function; dysregulated dermal homeostasis results in chronic wounds and fibrotic diseases. The multifunctional cytokine transforming growth factor (TGF) β promotes connective tissue deposition, repair, and fibrosis. TGF-β acts through well-defined canonical pathways; however, the non-canonical pathways through which TGF-β selectively promotes connective tissue deposition are unclear. In dermal fibroblasts, we show that inhibition of the non-canonical TGF-β-activated kinase 1 (TAK1) selectively reduced the ability of TGF-β to induce expression of a cohort of wound healing genes, such as collagens, CCN2, TGF-β1, and IL-6. Fibroblast-specific TAK1-knockout mice showed impaired cutaneous tissue repair and decreased collagen deposition, α-smooth muscle actin and CCN2 expression, proliferating cell nuclear antigen staining, and c-Jun N-terminal kinase and p38, but not Smad3, phosphorylation. TAK1-deficient fibroblasts showed reduced cell proliferation, migration, cell attachment/spreading, and contraction of a floating collagen gel matrix. TAK1-deficient mice also showed progressively reduced skin thickness and collagen deposition. Thus, TAK1 is essential for connective tissue deposition in the dermis.