Abstract
Impaired wound healing and ulceration represent a serious complication of both type 1 and type 2 diabetes. Cytoskeletal protein Flightless I (Flii) is an important inhibitor of wound repair, and reduced Flii gene expression in fibroblasts increased migration, proliferation, and adhesion. As such it has the ability to influence all phases of wound healing including inflammation, remodelling and angiogenesis. Flii has the potential to modulate inflammation through its interaction with MyD88 which it an adaptor protein for TLR4. To assess the effect of Flii on the inflammatory response of diabetic wounds, we used a murine model of streptozocin-induced diabetes and Flii genetic mice. Increased levels of Flii were detected in Flii transgenic murine wounds resulting in impaired healing which was exacerbated when diabetes was induced. When Flii levels were reduced in diabetic wounds of Flii-deficient mice, healing was improved and decreased levels of TLR4 were observed. In contrast, increasing the level of Flii in diabetic mouse wounds led to increased TLR4 and NF-κB production. Treatment of murine diabetic wounds with neutralising antibodies to Flii led to an improvement in healing with decreased expression of TLR4. Decreasing the level of Flii in diabetic wounds may therefore reduce the inflammatory response and improve healing.
Highlights
Up to 25% of people with diabetes can expect to develop a foot ulcer at some point in their lives [1]
Flightless I (Flii) has been identified as a protein that can inhibit the rate of healing by reducing the migration of keratinocytes and fibroblasts and limiting the degree of wound contraction [18, 22, 28]
Wound healing was impaired as Flii levels increased, and this impairment was exacerbated when diabetes was induced
Summary
Up to 25% of people with diabetes can expect to develop a foot ulcer at some point in their lives [1]. One area of research which has been shown to be integral to the wound repair process is that of the actin cytoskeleton which is a filamentous network found in all cells and facilitates processes such as cellular adhesion, migration and contraction [3, 4]. In addition to its role as a regulator of the cytoskeleton, the LRR domain allows Flii to bind a number of other proteins unrelated to actin including LRR Flii interacting proteins 1 and 2 (LLRFIP1 and LRRFIP2) and the double-stranded RNA binding protein TRIP [4, 9]. Flii is involved in numerous cellular activities including regulating transcription via coactivation of nuclear hormone
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