Oral Presentation ASDR-AWTRS-MEPSA 2018 Joint Meeting

Novel Approaches for Treatment of Dermatitis (#47)

Zlatko Kopecki 1 , Natalie Stevens 1 , Heng Chong 2 , Gink Yang 1 , Shireen Sidhu 3 , Jan Ibbetson 4 , Allison Cowin 1
  1. Future Industries Institute, University of South Australia, Adelaide, SA, Australia
  2. Discipline of Paediatrics, University of Adelaide, Adelaide, South Australia
  3. Royal Adelaide Hospital, Adelaide, SA, Australia
  4. Surgical Pathology Division, South Australia Pathology, Adelaide, SA, Australia

Inflammatory skin conditions psoriasiform dermatitis and atopic dermatitis affect up to 3% of Australian population and current therapeutic approaches have limited effect. These inflammatory skin conditions place a high burden on patient’s quality of life and are characterized by excessive inflammation, aberrant epidermal proliferation and disrupted skin barrier function. An actin remodelling protein, Flightless I (Flii), has been shown to promote inflammation and impair skin barrier development and function. Analysis of skin biopsies from patients with psoriasiform dermatitis (PD) showed increased Flii levels compared to healthy controls. We next sought to determine the effect of altering Flii expression on the development and/or treatment of dermatitis using murine models of atopic dermatitis (AD) and PD in Flii heterozygous (Flii+/-), wild-type (WT) and Flii transgenic (FliiTg/Tg) mice. Reduced Flii expression decreased the severity of Ovalbumin (OVA)-induced AD skin-like disease and was associated with reduced pro-inflammatory signalling and a marked IFN-γ Th1 response, while Flii over-expression lead to increased TNF-α cytokine production, elevated Th2 chemokine levels and increased Th2 cell numbers within affected skin. Sera from OVA-induced AD skin-like disease Flii+/- mice showed a decreased level of autoreactivity while sera from FliiTg/Tg mice counterparts showed an altered autoantibody profile with strong nuclear localization favouring development of a more severe disease. Decreasing Flii levels also significantly reduced tissue erythema, inflammatory cell infiltrate and thickness of epidermis in the Imiquimod-induced murine model of PD with concurrent decrease in pro-inflammatory cytokine release and TLR-4 expression. Additionally, topical application of Flii neutralising antibodies to skin of wild-type Imiquimod-treated mice significantly reduced PD skin-like disease severity and tissue inflammation. These findings suggest that Flii signalling promotes dermatitis symptoms and that reducing cutaneous Flii could represent a novel therapeutic approach for patients with dermatitis.