Fibroblast‐specific upregulation of Flightless I impairs wound healing

Abstract

The cytoskeletal protein Flightless (Flii) is a negative regulator of wound healing. Upregulation of Flii is associated with impaired migration, proliferation and adhesion of both fibroblasts and keratinocytes. Importantly, Flii translocates from the cytoplasm to the nucleus in response to wounding in fibroblasts but not keratinocytes. This cell-specific nuclear translocation of Flii suggests that Flii may directly regulate gene expression in fibroblasts, providing one potential mechanism of action for Flii in the wound healing response. To determine whether the tissue-specific upregulation of Flii in fibroblasts was important for the observed inhibitory effects of Flii on wound healing, an inducible fibroblast-specific Flii overexpressing mouse model was generated. The inducible ROSA26 system allowed the overexpression of Flii in a temporal and tissue-specific manner in response to tamoxifen treatment. Wound healing in the inducible mice was impaired, with wounds at day 7 postwounding significantly larger than those from non-inducible controls. There was also reduced collagen maturation, increased myofibroblast infiltration and elevated inflammation. The impaired healing response was similar in magnitude to that observed in mice with non-tissue-specific upregulation of Flii suggesting that fibroblast-derived Flii may have an important role in the wound healing response.

Delivery of Flightless I Neutralizing Antibody from Porous Silicon Nanoparticles Improves Wound Healing in Diabetic Mice

“…Statistical Analysis : Statistical differences were determined using the Student's t ‐test or an ANOVA. For data not following a normal distribution, the Mann–Whitney U‐test was performed . A P ‐value of less than 0.05 was considered significant.…”

Flightless I Expression Enhances Murine Claw Regeneration Following Digit Amputation

“…A decrease in Flii expression, either endogenously in heterozygous knockout mice or via the topical application of a neutralizing antibody raised against the leucine-rich repeat domain in murine and porcine wound models, results in improved healing (Cowin et al, 2007;Jackson et al, 2012;Strudwick and Cowin, 2012). Conversely, overexpression of Flii in the mouse resulted in larger scars, with a slower, impaired wound healing response (Cowin et al, 2007;Jackson et al, 2012;Strudwick and Cowin, 2012), with fibroblast-specific upregulation of Flii giving a similar magnitude of wound healing impairment to non-tissuespecific upregulation (Turner et al, 2015). However, Flii also has a positive effect on hair follicle regeneration, with Flii overexpression resulting in significantly longer hair fibers in regenerated follicles and reduced Flii expression resulting in delayed regeneration (Waters et al, 2011).…”

Reducing Flightless I expression decreases severity of psoriasis in an imiquimod-induced murine model of psoriasiform dermatitis

“…An in vitro study showed that Flii competes with MyD88 by binding to the TIR region of TLR4 and inhibits the formation of the TLR4/MyD88 signalling complex required for activation of cytokine secretion pathways . Flii expression in the skin is upregulated during development and in response to inflammation, tissue injury, skin cancer development and hypertrophic scarring . A recent study in an in vivo model of diabetic wound healing, showed that decreasing cutaneous Flii levels was associated with reduced inflammation and levels of TLR4 expression .…”