Strengthening the Skin Barrier by Using a Late Cornified Envelope 6A-Derived Biomimetic Peptide.

Changes in the expression of cornified envelope (CE) components are a hallmark of numerous pathological skin conditions and aging, underlying the importance of this stratum corneum structure in the homeostasis of the epidermal barrier. We performed a detailed characterisation of LCE6A, a member of the Late Cornified Envelope protein family. Immunohistochemical and immunoblot experiments confirmed that LCE6A is expressed late during epidermal differentiation.

Epidermal 1-O-acylceramides appear with the establishment of the water permeability barrier in mice and are produced by maturating keratinocytes.

1-O-Acylceramides (1-OACs) have a fatty acid esterified to the 1-hydroxyl of the sphingosine head group of the ceramide, and recently we identified these lipids as natural components of human and mouse epidermis. Here we show epidermal 1-OACs arise shortly before birth during the establishment of the water permeability barrier in mice. Fractionation of human epidermis indicates 1-OACs concentrate in the stratum corneum.

Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis.

Neonatal collodion baby or ichthyosis can pose a diagnostic challenge, and in many cases, only additional organ involvement or the course of the disease will help differentiate between non-syndromic and syndromic forms. Skin abnormalities are described in about 20% of the congenital disorders of glycosylation (CDG). Among those, some rare CDG forms constitute a special group among the syndromic ichthyoses and can initially misdirect the diagnosis towards non-syndromic genodermatosis.

Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds.

The role of epidermal proteolysis in overdesquamation was revealed in Netherton syndrome, a rare ichthyosis due to genetic deficiency of the LEKTI inhibitor of serine proteases. Recently, we developed activography, a new histochemical method, to spatially localize and semiquantitatively assess proteolytic activities using activity-based probes. Activography provides specificity and versatility compared to in situ zymography, the only available method to determine enzymatic activities in tissue biopsies.

PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide synthesis and skin permeability barrier.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of monogenic genodermatoses that encompasses non-syndromic disorders of keratinization. The pathophysiology of ARCI has been linked to a disturbance in epidermal lipid metabolism that impaired the stratum corneum function, leading to permeability barrier defects. Functional characterization of some genes involved in ARCI contributed to the identification of molecular actors involved in epidermal lipid synthesis, transport or processing.

Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects.

Background: Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood.

Objective: We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier.

Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis.

Twenty-six families with keratinopathic ichthyoses (epidermolytic ichthyosis, superficial epidermolytic ichthyosis or congenital reticular ichthyosiform erythroderma) were studied. Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. In this study mutations were found in KRT1, KRT2 and KRT10, including 8 mutations that are novel pathogenic variants.

Analysis of protein-protein interaction between late cornified envelope proteins and corneodesmosin.

Deletion of two members of the late cornified envelope (LCE) family, LCE3B and LCE3C (LCE3C_LCE3B-del), has been identified as risk factor for psoriasis with a possible role in skin barrier function. Moreover, genetic interaction between LCE3C_LCE3B-del and HLA-C*06, located in the psoriasis susceptibility regions 4 and 1 (PSORS4 and 1), has been reported in several populations. Because of high linkage disequilibrium between the PSORS1 genes HLA-C*06 and corneodesmosin (CDSN), both genes are potentially involved in psoriasis.

Mice deficient for the epidermal dermokine β and γ isoforms display transient cornification defects.

Expression of the human dermokine gene (DMKN) leads to the production of four dermokine isoform families. The secreted α, β and γ isoforms have an epidermis-restricted expression pattern, with Dmkn β and γ being specifically expressed by the granular keratinocytes. The δ isoforms are intracellular and ubiquitous.

Update on the epidermal differentiation complex.

On human chromosome 1q21, a 2-Mb region called the epidermal differentiation complex comprises many genes encoding structural and regulatory proteins that are of crucial importance for keratinocyte differentiation and stratum corneum properties. Apart from those for involucrin and loricrin, most of the genes are organized in four families: the genes encoding EF-hand calcium-binding proteins of the S100A family, the genes encoding the small proline rich proteins (SPRRs) and the late cornified envelope (LCE) proteins, two families of cornified cell envelope components, and the genes encoding the S100-fused type proteins (SFTPs). This review focuses on the SPRRs, LCE proteins and SFTPs.

Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses.

Corneodesmosin (CDSN) was identified 20 years ago by raising monoclonal antibodies against human plantar stratum corneum. The protein is specific to corneodesmosomes, cell-junction structures that, in humans, are found in the epidermis, the hard palate epithelium, and the inner root sheath of the hair follicles. Synthesized by the granular keratinocytes and secreted via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes, shortly before their transformation into corneodesmosomes during cornification.

The ubiquitous dermokine delta activates Rab5 function in the early endocytic pathway.

The expression of the recently identified dermokine (Dmkn) gene leads to four families of proteins with as yet unknown functions. The secreted α, β and γ isoforms share an epidermis-restricted expression pattern, whereas the δ isoform is intracellular and ubiquitous. To get an insight into Dmknδ function, we performed yeast two-hybrid screening and identified the small GTPases Rab5 as partners for Dmknδ.

A large-scale multi-technique approach identifies forty-nine new players of keratinocyte terminal differentiation in human epidermis.

At the latest stage of terminal differentiation in the epidermis, granular keratinocytes (GKs) undergo cornification, a programmed cell death required for the establishment of a functional skin barrier. A complex genetic regulatory network orchestrates the underlying biochemical modifications, but very few transcription factors specific to this programme have been identified to date. Here, we describe a large-scale, multi-technique approach performed on cells purified from normal human epidermis, primarily focusing on the identification of regulators.