Attenuation of Flightless I, an actin-remodelling protein, improves burn injury repair via modulation of transforming growth factor (TGF)-β1 and TGF-β3

• Published in: British journal of dermatology (1951) Vol. 161; no. 2; pp. 326 - 336
• Main Authors: Adams, D.H., Ruzehaji, N., Strudwick, X.L., Greenwood, J.E., Campbell, H.D., Arkell, R., Cowin, A.J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2009; Wiley-Blackwell
• Subjects: actin cytoskeleton; Biological and medical sciences; burn; Burns; collagen; Dermatology; Flightless I; Medical sciences; transforming growth factor-β; Traumas. Diseases due to physical agents; Dermatology; Transforming growth factor β; Flightless I; Protein; Burn; actin cytoskeleton; Actin; transforming growth factor-β; Collagen; Cytoskeleton; Transforming growth factor β1; bum; Repair
• ISSN: 0007-0963; 1365-2133
• DOI: 10.1111/j.1365-2133.2009.09296.x

Summary Background  The pathophysiological mechanisms involved in burn injury repair are still not fully understood but include processes involving cellular proliferation, migration and adhesion. The actin cytoskeleton is intricately involved in these key wound repair processes. Flightless I (Flii), an actin‐remodelling protein and transcriptional regulator, is an important regulator of wound healing. Objectives  To investigate the function of Flii gene expression in burn injury repair. Methods  Partial‐thickness scald wounds were created on Flii heterozygous (Flii+/−), wild‐type (WT) and Flii transgenic (FliiTg/+) mice. Burns were assessed using histology and immunohistochemistry, real‐time quantitative polymerase chain reaction and biochemical analysis. Results  Flii expression, while upregulated in burn injuries, was significantly lower in the wounds of Flii+/− vs. WT vs. FliiTg/+ mice and healing was improved in Flii+/− mice with their burns healing faster than WT and FliiTg/+. Pro‐scarring transforming growth factor (TGF)‐β1 protein and gene expression were reduced in Flii+/− burns while antiscarring TGF‐β3 was significantly elevated. Anti‐α‐smooth muscle actin (α‐SMA) was decreased in Flii+/− burns suggesting a decrease in contractile myofibroblasts in the developing scars. Although Flii is primarily a nuclear and cytoplasmic protein it is also released by wounded cells. Intradermal injection of Flii‐neutralizing antibodies (FliAbs) to WT burn wounds significantly improved their healing, indicating a potential novel approach for treating burns. Decreased TGF‐β1 and elevated TGF‐β3 expression were observed in FliAb‐treated burns, which may contribute to their observed improvement in healing. Conclusions  Strategies aimed at reducing Flii expression, for example using neutralizing antibodies, may lead to improved burn outcomes.