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

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 6; pp. 1538 - 1546.e6
• Main Authors: Kawasaki, Hiroshi, MD, Nagao, Keisuke, MD, PhD, Kubo, Akiharu, MD, PhD, Hata, Tsuyoshi, PhD, Shimizu, Atsushi, DVM, PhD, Mizuno, Hideaki, PhD, Yamada, Taketo, MD, PhD, Amagai, Masayuki, MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2012; Elsevier; Elsevier Limited
• Subjects: Allergic diseases; Allergy and Immunology; Animals; Atopic dermatitis; barrier function; Biological and medical sciences; Blood-Aqueous Barrier - metabolism; Cloning; Contact dermatitis; Degradation products; Dermatology; Dyskeratosis; Epithelium, Corneal - metabolism; Experiments; Filaggrin; filaggrin-null mice; flaky tail mice; Fluoresceins; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene targeting; Genes; Genotype; Haptens; Hydration; ichthyosis vulgaris; Immune response; Immunoglobulin E; Immunoglobulin G; Immunopathology; Inflammation; Intermediate Filament Proteins - deficiency; Intermediate Filament Proteins - genetics; Keratin; Keratins - metabolism; Mechanical properties; Medical sciences; Methods; Mice; Mice, Knockout; Mutation; Neonates; percutaneous immune response; Permeability; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Serum levels; Skin; Skin - immunology; Skin - pathology; Skin - ultrastructure; Skin allergic diseases. Stinging insect allergies; Stratum corneum; Stress; Water loss; Japan; FLG; Untranslated region; 1-Fluoro-2,4-dinitrobenzene; SPF; Tape stripping; atopic dermatitis; Filaggrin; percutaneous immune response; Murine filaggrin gene; Natural moisturizing factor; CHS; SC; stratum corneum; Desquamation index for amount; UTR; Specific pathogen free; SG; Human filaggrin gene; Flaky tail/matted; flaky tail mice; DIA; barrier function; Ovalbumin; TEWL; AD; Stratum granulosum; DNFB; NMF; ft/ma; filaggrin-null mice; Transepidermal water loss; ichthyosis vulgaris; IV; Transmission electron microscopy; OVA; TEM; Contact hypersensitivity; TS; Allergy; Dyskeratosis; Ichthyosis vulgaris; Immunopathology; Skin disease; Stratum corneum; Immune response; Barrier function; Hyperkeratosis; Rodentia; Atopy; Genetic disease; Percutaneous route; Vertebrata; Mammalia; Immunology; Mouse; Atopic dermatitis; Animal
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.01.068

Background 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 in vivo analysis of filaggrin’s functions. Objective We sought to generate Flg−/− mice and to assess the effect of filaggrin loss on SC barrier function and percutaneous immune responses. Methods 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. Results 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 IgG1 and IgE. Conclusion 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.