Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin-hornerin (FlgHrnr-/- ) double-deficient mice

Abstract

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.

Keywords: allergic contact dermatitis; filaggrin; hornerin; skin barrier.