Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen

doi:10.1016/j.jaci.2009.05.042

Journal of Allergy and Clinical Immunology

Volume 124, Issue 3, September 2009, Pages 485-493.e1

https://doi.org/10.1016/j.jaci.2009.05.042 Get rights and content

Background

Filaggrin is important for skin barrier function and is mutated in 15% to 20% of patients with atopic dermatitis.

Objective

To examine whether filaggrin deficiency predisposes to skin inflammation and epicutaneous sensitization with protein antigen.

Methods

Skin histology in filaggrin-deficient flaky tail (ft)/ft mice and wild-type controls was assessed by Hematoxylin and Eosin (H&E) staining and immunohistochemistry. Cytokine mRNA expression was examined by quantitative RT-PCR. Serum antibody levels and splenocyte secretion of cytokines were measured by ELISA.

Results

The ft/ft mice developed eczematous skin lesions after age 28 weeks and a progressive increase in serum IgE and IgG₁ levels. Normal-appearing skin from 8-week-old ft/ft mice had epidermal thickening and increased dermal infiltration with CD4⁺ cells and expression of mRNA for IL-17, IL-6, and IL-23, but not IL-4, IL-13, or IFN-γ. Lesional skin of 32-week-old ft/ft mice exhibited qualitatively similar, but more pronounced, changes, and elevated IL-4 mRNA levels. Epicutaneous application of ovalbumin to shaved skin of 8-week-old ft/ft mice, but not WT mice, resulted in increased epidermal thickening, dermal infiltration by CD4⁺ cells but not eosinophils, and expression of IL-17, IL-6, IL-23, IL-4, and IFN-γ, but not IL-5 or IL-13, mRNA. Splenocytes from epicutaneously sensitized ft/ft mice, but not controls, secreted cytokines in response to ovalbumin stimulation, and their sera, but not those of controls, contained ovalbumin-specific IgE and IgG₁ antibodies.

Conclusion

Filaggrin-deficient mice exhibit T_H17-dominated skin inflammation and eczematous changes with age, and are permissive to epicutaneous sensitization with protein antigen.

Section snippets

Mice

Flaky tail mice were purchased from Jackson Laboratory (Bar Harbor, Maine). C57BL6 and BALB/c wild-type (WT) mice were from Charles River Laboratories (Wilmington, Mass). All mice were bred in our animal facility, kept in a specific pathogen-free environment, and fed an ovalbumin-free diet. All procedures performed on the mice were in accordance with the Animal Care and Use Committee of the Children's Hospital Boston.

Epicutaneous sensitization and intraperitoneal immunization

The skin of anesthetized 8-week-old female mice was shaved. Then 100 μg

The ft/ft mice develop eczematous skin lesions

Neonatal ft/ft mice appear normal at birth but have increased TEWL.¹⁸ The flaky tail phenotype appears at about 3 days of age with the skin having a dry, scaly appearance.¹⁵ There is gradual improvement of the skin condition, and 3-week-old ft/ft pups appear normal, except for shortened ears and loss of tail tips in some mice. Because ft/ft mice are not on a homogenous C57BL6 background, we used both C57BL6 and BALB/c mice as controls. These 2 strains lie on opposite ends of the spectrum of T_H

Discussion

We demonstrate that filaggrin deficiency is associated with T_H17-dominated skin inflammation, development of eczematous skin lesions with age, and permissiveness to epicutaneous sensitization with protein antigen.

Except for matted hair, there were no discernible skin lesions in ft/ft mice until about 28 weeks of age. By 32 weeks of age, ft/ft mice developed scaly eczematous skin lesions (Fig 1, A). Skin lesions have not been previously described in ft/ft mice,¹⁸ possibly because previous

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: Supported by the Atopic Dermatitis and Vaccinia Immunization Network, contract NO1 AI 40030, and USPHS grant AR-047417.

: Disclosure of potential conflict of interest: G. F. Murphy has received research support from the National Institutes of Health. The rest of the authors have declared that they have no conflict of interest.

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Atopic dermatitis and skin diseaseFilaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen

Background

Objective

Methods

Results

Conclusion

Section snippets

Mice

Epicutaneous sensitization and intraperitoneal immunization

The ft/ft mice develop eczematous skin lesions

Discussion

Lancet

J Dermatol Sci

J Allergy Clin Immunol

J Invest Dermatol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Invest Dermatol

J Invest Dermatol

J Biol Chem

Curr Opin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin

Acta Derm Venereol

Factors associated with the development of peanut allergy in childhood

N Engl J Med

Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge

Proc Natl Acad Sci U S A

The immunogenetics of asthma and eczema: a new focus on the epithelium

Nat Rev Immunol

Moisturization and skin barrier function

Dermatol Ther

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

Nat Genet

Atopic dermatitis and skin disease
Filaggrin-deficient mice exhibit T_H17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen