Poster Presentation 2014 Cutaneous Biology Meeting

Decreasing Flightless I reduces erythema and inflammation in an mouse model of psoriasis (#18)

Heng Teck Chong 1 , Gink N Yang 2 , Jan S Ibbetson 3 , Shireen Sidhu 4 , Zlatko Kopecki 1 2 , Allison J Cowin 1 2
  1. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia
  2. Centre for Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, South Australia, Australia
  3. Surgical Pathology Division, SA Pathology, Adelaide, South Australia, Australia
  4. Department of Dermatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia

Psoriasis is a common chronic skin condition characterised by excessive inflammation and aberrant epidermal proliferation. The remodelling of the actin cytoskeleton has been shown to mediate the inflammatory responses and contributes to disease pathogenesis. The actin remodelling protein, Flightless I (Flii) can regulate tissue inflammation via its effects on Toll-like Receptor signalling. Here we investigated the effect of psoriasis on Flii levels in human biopsies and determined if changing the expression of Flii in an in vivo mouse model reduced the severity of this skin condition.  Biopsies from psoriatic lesions of patients showed elevated expression of Flii compared to normal human skin. Using Flii heterozygous (Flii+/-), wild-type (Flii+/+) and Flii transgenic (FliiTg/Tg) mice in a topical imiquimod (TLR 7 agonist) murine model of psoriasis, we showed that mice with reduced levels of Flii had less severed psoriasis, decreased erythema and reduced inflammation characterised by decreased  secretion of proinflammatory cytokines including: IL-17A, NF-ƙB and TNF-α. In contrast, over expression of Flii resulted in increased inflammation and epidermal proliferation as evidenced by thinner epidermis; shorter rete pegs lengths and increased number of PCNA positive keratinocytes. Flii neutralising antibodies (FnAb) (50µg/ml in cream vehicle) applied  topically to the skin 3 days before induction of psoriasis and daily for the duration of the experiment decreased erythema and skin thickening and reduced the inflammatory response.  In conclusion, Flii is elevated in the lesions of patients with psoriasis and over expression of Flii in a mouse model increases the severity of this skin condition. Reducing Flii both genetically and using a monoclonal antibody improves the symptoms associated with this skin condition.

  1. Cowin AJ, Lei N, Franken L, Ruzehaji N, Offenhauser C, Kopecki Z, et al. Lysosomal secretion of Flightless I upon injury has the potential to alter inflammation. Communicative & integrative biology. 2012;5(6):546-9
  2. Chong HT, Kopecki Z, Cowin AJ. Lifting the silver flakes: the pathogenesis and management of chronic plaque psoriasis. BioMed research international. 2013;2013:168321
  3. Cowin AJ, Adams DH, Strudwick XL, Chan H, Hooper JA, Sander GR, et al. Flightless I deficiency enhances wound repair by increasing cell migration and proliferation. The Journal of pathology. 2007;211(5):572-81