LB962 Loss of transcription factor Ovol1 enhances IMQ-induced psoriasis-like skin defects

Abstract

The contribution of epidermal-intrinsic mechanisms to inflammatory skin diseases has been increasingly recognized. In particular, a defective epidermal permeability barrier is associated with both atopic dermatitis and psoriasis – two common inflammatory diseases with devastating skin manifestations – and underlying genetic mutations affecting structural components of the epidermal barrier have been identified. OVOL1 is the first transcription factor-encoding gene with mutations identified in multiple inflammatory skin diseases including atopic dermatitis. However, its functional involvement in such diseases has not been examined. Our previous study has uncovered a role for Ovol1 in embryonic epidermal morphogenesis, as its deletion results in failure of epidermal progenitor cells to efficiently undergo growth arrest. Here we show that Ovol1 expression is specific to epidermal cells of the adult skin, and is altered under diseased conditions. We provide evidence that adult Ovol1 null mice exhibit exacerbated atopic dermatitis-like and psoriasis-like skin lesions upon treatment with MC903 and imiquimod, respectively. In both cases, Ovol1-deficient epidermis launches a faster and/or more severe hyperproliferative response than control littermates. Further analysis of the imiquimod model reveals dramatically more severe inflammatory responses in Ovol1 knockout mice, including neutrophil migration and accumulation to the skin surface and upregulated expression of inflammatory cytokines and chemokines. Although neutrophil depletion relieves imiquimod-induced psoriatic appearance in Ovol1-deficient mice, it does not significantly improve epidermal hyperproliferation. Current work addresses the molecular and cellular mechanisms of Ovol1 involvement, and data will be presented.