Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.
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 IgG(1) 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-gamma. 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-gamma, 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 IgG(1) antibodies.


CONCLUSIONS
Filaggrin-deficient mice exhibit T(H)17-dominated skin inflammation and eczematous changes with age, and are permissive to epicutaneous sensitization with protein antigen.
Oyoshi
Michiko K
MK
Division of Immunology, Department of Pediatrics, Harvard Medical School, Children's Hospital, Boston, Mass 02115, USA.
Murphy
George F
GF
Geha
Raif S
RS
D000485:Allergens / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D000091344:Filaggrin Proteins; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007381:Intermediate Filament Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
D000485:Allergens; D016207:Cytokines; D000091344:Filaggrin Proteins; D007074:Immunoglobulin G; D007381:Intermediate Filament Proteins; D007073:Immunoglobulin E; D010047:Ovalbumin