Regional Differences in the Permeability Barrier of the Skin—Implications in Acantholytic Skin Diseases

The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier’s disease, and Hailey–Hailey disease).

The Interactions of Small Proline-rich Proteins With Late Cornified Envelope Proteins Are Involved in the Pathogenesis of Psoriasis

Background: Psoriasis is a common cutaneous disease with many characteristics including inflammation and aberrant keratinocyte proliferation. However, the pathogenesis of psoriasis is not completely clear. Methods: We explore the differentially expressed genes (DEGs) in psoriasis by analyzing the gene expression profile obtained from the Gene Expression Omnibus (GEO) database. The DEGs were examined by gene ontology (GO) functional enrichment analysis and protein-protein interactions (PPI) network. Correlation analysis in R studio software analyzed the association of SPRR and LCE genes. The potential direct protein-protein interactions between SPRR proteins and LCE3D was further verified by co-localization observed in 293T cells and co-immunoprecipitation (CO-IP). The expression levels of SPRR and LCE genes were detected in the IMQ-induced psoriasiform dermatitis mice. Results: The small proline-rich (SPRR) and late cornified envelope (LCE) genes were identified as a module in constructed PPI network. The gene expression profile GSE63684 analysis showed that both SPRR family and LCE family genes were significantly upregulated in imiquimod (IMQ) induced psoriasiform dermatitis mice. Correlation analysis in R studio software recognized the association of SPRR and LCE genes, in which the potential direct protein-protein interactions between SPRR proteins and LCE3D was further verified by co-localization observed in 293T cells and co-immunoprecipitation (CO-IP) results that suggest direct interaction between SPRR2 and LCE3D. Notably, we found that the expression levels of SPRR and LCE genes were significantly increased in the IMQ-induced psoriasiform dermatitis mice while tazarotene cream treatment specifically decreased the mRNA expression of these genes, which indicated that the SPRR and LCEs were regulated simultaneously in psoriasis. Conclusion: Our studies found the interactions of SPRR proteins with LCE proteins, which may provide new insights into the pathogenesis of psoriasis.

Gene duplications and gene loss in the epidermal differentiation complex during the evolutionary land-to-water transition of cetaceans

Major protein components of the mammalian skin barrier are encoded by genes clustered in the Epidermal Differentiation Complex (EDC). The skin of cetaceans, i.e. whales, porpoises and dolphins, differs histologically from that of terrestrial mammals. However, the genetic regulation of their epidermal barrier is only incompletely known. Here, we investigated the EDC of cetaceans by comparative genomics. We found that important epidermal cornification proteins, such as loricrin and involucrin are conserved and subtypes of small proline-rich proteins (SPRRs) are even expanded in numbers in cetaceans. By contrast, keratinocyte proline rich protein (KPRP), skin-specific protein 32 (XP32) and late-cornified envelope (LCE) genes with the notable exception of LCE7A have been lost in cetaceans. Genes encoding proline rich 9 (PRR9) and late cornified envelope like proline rich 1 (LELP1) have degenerated in subgroups of cetaceans. These data suggest that the evolution of an aquatic lifestyle was accompanied by amplification of SPRR genes and loss of specific other epidermal differentiation genes in the phylogenetic lineage leading to cetaceans.

Corneocytes: Relationship between Structural and Biomechanical Properties

<b><i>Background:</i></b> Skin is the interface between an organism and the external environment, and hence the stratum corneum (SC) is the first to withstand mechanical insults that, in certain conditions, may lead to integrity loss and the development of pressure ulcers. The SC comprises corneocytes, which are vital elements to its barrier function. These cells are differentiated dead keratinocytes, without organelles, composed of a cornified envelope and a keratin-filled interior, and connected by corneodesmosomes (CDs). <b><i>Summary:</i></b> The current review focusses on the relationship between the morphological, structural, and topographical features of corneocytes and their mechanical properties, to understand how they assist the SC in maintaining skin integrity and in responding to mechanical insults. <b><i>Key Messages:</i></b> Corneocytes create distinct regions in the SC: the inner SC is characterized by immature cells with a fragile cornified envelope and a uniform distribution of CDs; the upper SC has resilient cornified envelopes and a honeycomb distribution of CDs, with a greater surface area and a smaller thickness than cells from the inner layer. The literature indicates that this upward maturation process is one of the most important steps in the mechanical resistance and barrier function of the SC. The morphology of these cells is dependent on the body site: the surface area in non-exposed skin is about 1,000–1,200 μm², while for exposed skin, for example, the cheek and forehead, is about 700–800 μm². Corneocytes are stiff cells compared to other cellular types, for example, the Young’s modulus of muscle and fibroblast cells is typically a few kPa, while that of corneocytes is reported to be about hundreds of MPa. Moreover, these skin cells have 2 distinct mechanical regions: the cornified envelope (100–250 MPa) and the keratin matrix (250–500 MPa).