Filaggrin-deficiency drives immunopathogenic IL-18 response during in the initiation of atopic dermatitis 2256840

Introduction The skin forms a mechanical barrier against invading pathogens and environmental allergens. As such, genetic deficiencies in crucial barrier proteins such as filaggrin could result in skin barrier dysfunction. Clinically, filaggrin deficiency is correlated with predisposition to ichthyosis vulgaris (IV), increasing severity to atopic dermatitis (AD) and susceptibility to cutaneous infections. However, immunological mechanisms of how filaggrin-deficiency drives these skin disorders and augment the interactions with microbes remain unclear. Methods Using a mouse model with specific deficiency for filaggrin, we topically administered the ears with MC903 and colonized with Staphylococcus aureus to interrogate the effects on atopic dermatitis and pathobiontic bacterial colonization. Results We first show that filaggrin-deficiency results in comparable trans-epidermal water loss (TEWL) at baseline. However, filaggrin deficient (Flg-/-) mice exhibited increased inflammation and barrier dysfunction upon a biophysical challenge such as tape-stripping. Post atopic induction with calcipotriol (MC903) challenge, elevated tissue swelling and TEWL were also observed in Flg-/- animals relative to wildtype (WT) mice. The proinflammatory cytokine- IL18 was also significantly upregulated in Flg-/- mice compared to WT. Importantly, prophylactic inhibition of IL-18 significantly reduced skin swelling and restored barrier function in filaggrin-deficient mice to WT levels, underscoring its potential as a therapeutic target for inhibition during AD. Moreover, IL-18 expression was elevated in the keratinocytes in our mouse model of AD and in human AD patients. Colonization of filaggrin-deficient mice with S.aureus also resulted in the elevation of inflammatory swelling compared to WT controls. Conclusion We have thus described an animal model of skin barrier dysfunction with filaggrin-deficient mice to study the initiation events of disease and identified IL-18 as an immunopathogenic factor during atopic dermatitis. Funding Source Skin Research Institute of Singapore Joint Research Grant (SRIS_JRG_2010)