Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin-hornerin (FlgHrnr −/− ) double-deficient mice
| Autor: | Martin Mempel, Timo Buhl, Judith M. Dettmann, Andrea Braun, Sebastian Rahrig, Peter M. Elias, Sanja Kezic, Birka Brauns, Verena N. Lorenz, Stephan Weidinger, Michael P. Schön |
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| Přispěvatelé: | Coronel Institute of Occupational Health, APH - Personalized Medicine, APH - Societal Participation & Health |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chemistry Immunology Atopic dermatitis medicine.disease Phenotype 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system medicine.anatomical_structure 030228 respiratory system medicine Stratum corneum Immunology and Allergy Allergic contact dermatitis Hapten Gene Filaggrin |
| Zdroj: | Allergy, 74(7), 1327-1339. Wiley-Blackwell |
| ISSN: | 0105-4538 |
| DOI: | 10.1111/all.13756 |
| Popis: | Background: Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss-of-function mutations of these genes constitute a risk factor for atopic dermatitis and eczema-related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation. Methods: By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double-deficient (FlgHrnr −/− ) mouse model lacking both genes including the intergenomic sequence. Results: Neonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnr −/− mice displayed a markedly reduced granular layer and a condensed cornified layer. Functionally, FlgHrnr −/− mice showed permeability abnormalities and metabolic aberrations regarding the production of natural moisturizing factors (NMFs) in the stratum corneum. Surprisingly, although the immune system revealed no aberrations under steady-state conditions, FlgHrnr −/− mice are predisposed to mount an allergic contact dermatitis, especially at hapten threshold levels eliciting allergic reactions. Conclusions: Together, our FlgHrnr −/− mouse model nicely reflects the epicutaneous sensitization susceptibilities and inflammatory reactions to environmental insults in humans with impaired skin barrier functions. |
| Databáze: | OpenAIRE |
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