title: The influence of Flightless I on Toll-like-receptor-mediated inflammation in a murine model of diabetic wound healing.
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- κ B 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.
authors.affiliation: Wound Healing Laboratory, Women's & Children's Health Research Institute, 72 King William Road, North Adelaide, Adelaide, SA 5006, Australia.
authors.forename: Nadira
authors.initials: N
authors.lastname: Ruzehaji
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Mills
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Melville
authors.forename: Ruth
authors.initials: R
authors.lastname: Arkell
authors.forename: Robert
authors.initials: R
authors.lastname: Fitridge
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Cowin
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014945:Wound Healing / Q000235:genetics; D014947:Wounds and Injuries / Q000139:chemically induced
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000609263:FlII protein, mouse; D008840:Microfilament Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015534:Trans-Activators
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