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 steadystate 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. K E Y W O R D S allergic contact dermatitis, filaggrin, hornerin, skin barrier S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Rahrig S, Dettmann JM, Brauns B, et al. Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin-hornerin (FlgHrnr −/− ) double-deficient mice. Allergy.

Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses

“…We identified a set of genes that are statistically differentially expressed only between chronic and acute lesions, while showing little changes between acute and nonlesional AD (Fig 2, B-D). These include genes that participate in skin barrier maintenance and repair (HRNR), IL-20, [14][15][16] immunoglobulin production (IGHG1, IGLC2, IGKC), inhibition of CD4 1 T-cell activation (CLEC3A), 17 and tryptophan metabolism (KYNU). 18 It is noteworthy that the immunoglobulins as a group have been identified as differentially expressed in chronic lesional skin of psoriasis and AD 8 ; in addition, KYNU, the L-kynureninase, which regulates tryptophan metabolism, can serve as an immune response modulator for chronic inflammatory conditions.…”

Filaggrin Expression and Processing Deficiencies Impair Corneocyte Surface Texture and Stiffness in Mice

“…Mouse models and collected SC samples, including age of mice, are shown in Table 1. Phenotypes of mice have previously been reported (Borowczyk et al, 2012;Fallon et al, 2009;Rahrig et al, 2019;Saunders et al, 2013;Schwartz et al, 1999;Suszy nska-Zajczyk et al, 2014;) and summarized in Supplementary Materials and Methods. Briefly, immediately after birth (P0), FlgHrnr À/À mice were indistinguishable from neonatal wild-type controls, but from day 4 (P4) deficient mice developed an overall flaky appearance with dry, shiny skin and peeling all over the body, particularly on the back.…”

Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000‐2015: a retrospective multicentre study

“…One explanation could be that patients with epidermal deficiency of, for example, FLG and/or Hrnr exhibit not only more, but also a stronger patch test reaction to aeroallergens. 50,57 Thus, these results speak against the generalizing interpretation of aeroallergen patch test reactions as irritant or unspecific in AD patients, 59 even though there is no morphological way to distinguish a weak irritant reaction from a weak allergic reaction. 60,61 Largely independent of AD status, our data confirm previous results suggesting a role for patch testing HDM and pollen allergens in patients with respiratory allergy, 19,62 especially when there is a positive history for AR.…”

“…15,16 An increased aeroallergen responsiveness in patients with AD might be mediated by a combination of increased epidermal penetration through the impaired physical barrier and steady-state inflammation found in, for example filaggrin (FLG) and/or hornerin (Hrnr) deficient skin. [50][51][52] The possible result is an increased access of aeroallergens to Langerhans and inflammatory dendritic epidermal cells with a selective upregulation of the T h 2 immune response. 2,4,53,54 As patients with AD tend to have more frequent irritant or false-positive reactions to commonly tested haptens, [55][56][57][58] it was of special importance to assess the reaction profiles of the distinct aeroallergen patch test preparations.…”