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
Enthalten in: ALLERGY
Band: 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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