Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin-hornerin (FlgHrnr(-/-)) double-deficient mice
Autor(en): | Rahrig, Sebastian Dettmann, Judith M. Brauns, Birka Lorenz, Verena N. Buhl, Timo Kezic, Sanja Elias, Peter M. Weidinger, Stephan Mempel, Martin Schoen, Michael P. Braun, Andrea |
Stichwörter: | allergic contact dermatitis; Allergy; ATOPIC-DERMATITIS; ECZEMA; filaggrin; GENE; hornerin; ICHTHYOSIS VULGARIS; Immunology; MODEL; NATURAL MOISTURIZING FACTOR; OF-FUNCTION MUTATIONS; RISK-FACTORS; SKIN; skin barrier; STRATUM-CORNEUM | Erscheinungsdatum: | 2019 | Herausgeber: | WILEY | Journal: | ALLERGY | Volumen: | 74 | Ausgabe: | 7 | Startseite: | 1327 | Seitenende: | 1339 | Zusammenfassung: | 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. |
ISSN: | 01054538 | DOI: | 10.1111/all.13756 |
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geprüft am 01.06.2024