Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice

Abstract

Loss-of-function mutations in filaggrin are major predisposing factors for atopic dermatitis. Although various reports suggest a critical role for filaggrin in stratum corneum (SC) barrier formation, the lack of filaggrin-null (Flg(-/-)) mice has hampered detailed invivo analysis of filaggrin's functions. We sought to generate Flg(-/-) mice and to assess the effect of filaggrin loss on SC barrier function and percutaneous immune responses. We generated Flg(-/-) mice using gene targeting and assessed the morphology, hydration, mechanical strength, and antigen permeability of their SC. Percutaneous immune responses were evaluated through irritant- and hapten-induced contact hypersensitivity studies and by measuring humoral responses to epicutaneous sensitization with protein antigen. Newborn Flg(-/-) mice exhibited dry scaly skin. Despite marked decreases in natural moisturizing factor levels, which are filaggrin degradation products, SC hydration and transepidermal water loss were normal. Microscopic analyses suggested premature shedding of SC layers, and indeed, increased desquamation under mechanical stress was demonstrated. Loss of keratin patterns, which are critical for corneocyte stabilization, is likely attributable to fragility in the Flg(-/-) SC. Antigens penetrated the Flg(-/-) SC more efficiently, leading to enhanced responses in hapten-induced contact hypersensitivity and higher serum levels of anti-ovalbumin IgG(1) and IgE. Complete filaggrin deficiency led to altered barrier integrity and enhanced sensitization, which are important factors in early-phase atopic dermatitis. Flg(-/-) mice should provide a valuable tool to further explore additional factors the dysfunction of which leads to uncontrolled inflammation in patients with atopic diseases.