Epidermal Permeability Barrier Research Articles

Diesel particulate matter permeation into normal human skin and intervention using a topical ceramide formulation.

Diesel particulate matter (DPM) emitted from diesel engines is a major source of air pollutants. DPM is composed of elemental carbon, which adsorbs organic compounds including toxic polycyclic aromatic hydrocarbons (PAH). The skin, as well as airways, are directly exposed to DPM, and association of atopic dermatitis, psoriasis flares, and premature skin aging with air pollutant levels has been documented. In skin, the permeation of DPM and DPM-adsorbed compounds is primarily blocked by the epidermal permeability barrier deployed in the stratum corneum. Depending upon the integrity of this barrier, certain amounts of DPM and DPM-adsorbed compounds can permeate into the skin. However, this permeation into human skin has not been completely elucidated. We assessed the permeation of PAHs (adsorbed to DPM) into skin using ex vivo normal (barrier-competent) organ-cultured human skin after application of DPM. Two major PAHs, 2-methylnaphthalene and triphenylene, and a carcinogenic polycyclic aromatic hydrocarbon (PAH), benzo(a)pyrene, all found in DPM, were measured in the epidermis and dermis using liquid chromatography electrospray ionization tandem mass spectrometry. In addition, we investigated whether a topical formulation can attenuate the permeation of DPM into skin. 2-methylnaphthalene, triphenylene and benzo(a)pyrene were recovered from the epidermis. Although these PAH were also detected in the dermis after DPM application, these PAH levels were significantly lower than those found in the epidermis. We also demonstrated that a topical formulation that has the ability to form more uniform membrane structures can significantly suppress the permeation of PAH adsorbed to DPMs into the skin. Toxic compounds adsorbed by DPM can permeate even barrier-competent skin. Hence, barrier-compromised skin, such as in atopic dermatitis, psoriasis and xerosis, is even more vulnerable to air pollutants. A properly formulated topical mixture that forms certain membrane structures on the skin surface can effectively prevent permeation of exogenous substances, including DPM, into skin.

MiRNA-224-5p regulates the defective permeability barrier in sensitive skin by targeting claudin-5.

Sensitive skin is hypersensitive to various external stimuli and a defective epidermal permeability barrier is an important clinical feature of sensitive skin. Claudin-5 (CLDN5) expression levels decrease in sensitive skin. This study aimed to explore the impact of CLDN5 deficiency on the permeability barrier in sensitive skin and the regulatory role of miRNAs in CLDN5 expression. A total of 26 patients were retrospectively enrolled, and the CLDN5 expression and permeability barrier dysfunction in vitro were assessed. Then miRNA-224-5p expression was also assessed in sensitive skin. Immunofluorescence and electron microscopy revealed reduced CLDN5 expression, increased miR-224-5p expression, and disrupted intercellular junctions in sensitive skin. CLDN5 knockdown was associated with lower transepithelial electrical resistance (TEER) and Lucifer yellow penetration in keratinocytes and organotypic skin models. The RNA-seq and qRT-PCR results indicated elevated miR-224-5p expression in sensitive skin; MiR-224-5p directly interacted with the 3`UTR of CLDN5, resulting in CLDN5 deficiency in the luciferase reporter assay. Finally, miR-224-5p reduced TEER in keratinocyte cultures. These results suggest that the miR-224-5p-induced reduction in CLDN5 expression leads to impaired permeability barrier function, and that miR-224-5p could be a potential therapeutic target for sensitive skin.

The water extracts from the oil cakes of Prinsepia utilis repair the epidermal barrier via up-regulating Corneocyte Envelope-proteins, lipid synthases, and tight junction proteins

Ethnopharmacological relevancePrinsepia utilis Royle, native to the Himalayan region, has a long history of use in traditional medicine for its heat-clearing, detoxification, anti-inflammatory, and analgesic properties. Oils extracted from P. utilis seeds are also used in cooking and cosmetics. With the increasing market demand, this extraction process generates substantial industrial biowastes. Recent studies have found many health benefits with using aqueous extracts of these biowastes, which are also rich in polysaccharides. However, there is limited research related to the reparative effects of the water extracts of P. utilis oil cakes (WEPUOC) on disruptions of the skin barrier function. Aim of the studyThis study aimed to evaluate the reparative efficacy of WEPUOC in both acute and chronic epidermal permeability barrier disruptions. Furthermore, the study sought to explore the underlying mechanisms involved in repairing the epidermal permeability barrier. Materials and methodsMouse models with induced epidermal disruptions, employing tape-stripping (TS) and acetone wiping (AC) methods, were used. The subsequent application of WEPUOC (100 mg/mL) was evaluated through various assessments, with a focus on the upregulation of mRNA and protein expression of Corneocyte Envelope (CE) related proteins, lipid synthase-associated proteins, and tight junction proteins. ResultsThe polysaccharide was the major phytochemicals of WEPUOC and its content was determined as 32.2% by the anthranone-sulfuric acid colorimetric method. WEPUOC significantly reduced transepidermal water loss (TEWL) and improved the damaged epidermal barrier in the model group. Mechanistically, these effects were associated with heightened expression levels of key proteins such as FLG (filaggrin), INV (involucrin), LOR (loricrin), SPT, FASN, HMGCR, Claudins-1, Claudins-5, and ZO-1. ConclusionsWEPUOC, obtained from the oil cakes of P. utilis, is rich in polysaccharides and exhibits pronounced efficacy in repairing disrupted epidermal barriers through increased expression of critical proteins involved in barrier integrity. Our findings underscore the potential of P. utilis wastes in developing natural cosmetic prototypes for the treatment of diseases characterized by damaged skin barriers, including atopic dermatitis and psoriasis.

Preventive and Therapeutic Benefits of Natural Ingredients in Photo-Induced Epidermal Dysfunction.

The skin, particularly the epidermis, is subjected to various external stresses, including ultraviolet [UV] irradiation. UV irradiation, mainly UVB at wavelength of 280-315 nm, can alter several epidermal functions, including cutaneous inflammation, epidermal hyperproliferation, DNA damage, disruption of epidermal permeability barrier and reduction in stratum corneum hydration levels. Because of the negative impacts of UVB irradiation on epidermal functions, great efforts have been made to develop regimens for the protection of alterations in epidermal function induced by UV irradiation. While sunscreen can provide physical barrier to UV light, some natural ingredients can also effectively protect the skin from UVB irradiation-induced damages. Studies have demonstrated that either topical or oral administrations of some natural ingredients attenuate UVB irradiation-induced alterations in the epidermal function. The underlying mechanisms by which natural ingredients improve epidermal functions are attributable to antioxidation, stimulation of keratinocyte differentiation, increases in the content of epidermal natural moisturizers and inhibition of inflammation. Some natural ingredients exhibit protective and therapeutical benefits in photo-induced epidermal dysfunctions via divergent mechanisms.

Applications of nitric oxide-releasing nanomaterials in dermatology: Skin infections and wound healing

Nitric oxide (NO) is produced in most cells in the skin and is an important regulator of essential cutaneous functions, including responses to UV irradiation, microbial defense, wound healing, melanogenesis and epidermal permeability barrier homeostasis. Harnessing the physiological activities of NO for therapeutic use is difficult because the molecule is highly reactive and unstable. A variety of exogenous NO delivery platforms have been developed and evaluated; however, they have limited clinical applications in dermatology due to instability and poor cutaneous penetration. NO-releasing nanomaterials overcome these limitations, providing targeted tissue delivery, and sustained and controlled NO release. This review provides a comprehensive and up-to-date evaluation of the use of NO-releasing nanomaterials in dermatology for the treatment of skin and soft tissue infections and wound healing.

Benefits of topical natural ingredients in epidermal permeability barrier.

Because of the crucial role of epidermal permeability barrier in regulation of cutaneous and extracutaneous functions, great efforts have been made to identify and develop the regimens that can improve epidermal permeability barrier function. Studies have demonstrated that oral administration of natural ingredients can improve epidermal permeability barrier in various skin conditions, including inflammatory dermatoses and UV-irradiation. Moreover, topical applications of some natural ingredients can also accelerate the repair of epidermal permeability barrier after acute barrier disruption and lower transepidermal water loss in the intact skin. Natural ingredient-induced improvements in epidermal permeability barrier function can be attributable to upregulation of keratinocyte differentiation, lipid production, antioxidant, hyaluronic acid production, expression of aquaporin 3 and sodium-hydrogen exchanger 1. In this review, we summarize the benefits of topical natural ingredients in epidermal permeability barrier in normal skin with or without acute barrier disruption and the underlying mechanisms.

Barrier Abnormalities in Type 1 Diabetes Mellitus: The Roles of Inflammation and Ceramide Metabolism

Xerosis is a common sign of both type 1 and type 2 diabetes mellitus (DM), and patients with DM and mouse models for DM show a compromised epidermal permeability barrier. Barrier defects then allow the entry of foreign substances into the skin, triggering inflammation, infection, and worsening skin symptoms. Characterizing how barrier abnormalities develop in DM could suggest treatments for xerosis and other skin disease traits. Because the proper ratio, as well as proper bulk amounts, of heterogeneous ceramide species are keys to forming a competent barrier, we investigated how ceramide metabolism is affected in type 1 DM using a mouse model (induced by streptozotocin). Chronic inflammation, evident in the skin of mice with DM, leads to (i) decreased de novo ceramide production through serine racemase activation-mediated attenuation of serine palmitoyl transferase activity by D-serine; (ii) changes in ceramide synthase activities and expression that modify the ratio of ceramide molecular species; and (iii) increased ceramide-1-phosphate, a proinflammatory lipid mediator, that stimulates inflammatory cytokine expression (TNFα and IFN-γ). Together, chronic inflammation affects ceramide metabolism, which attenuates epidermal permeability barrier formation, and ceramide-1-phosphate could amplify this inflammation. Alleviation of chronic inflammation is a credible approach for normalizing barrier function and ameliorating diverse skin abnormalities in DM.

Rosacea and seborrheic dermatitis differentially respond to lactic acid sting and capsaicin tests in Chinese women.

Although rosacea and seborrheic dermatitis share some symptoms of sensitive skin, whether they respond differently to lactic acid sting and capsaicin tests, common tests for diagnosis of sensitive skin, is unknown. To reveal the cutaneous responses to lactic acid sting (LAST) and capsaicin test (CAT) in females with either rosacea vs. seborrheic dermatitis. A total of 60 patients with rosacea, 20 patients with seborrheic dermatitis and 40 normal controls were enrolled in the study. Their skin sensitivity to stimuli were evaluated following topical application of either 10% lactic acid solution or 0.001% capsaicin solution. Transepidermal water loss (TEWL) rates and erythema indexes were also measured on the face. In comparison to normal controls, the positive rate to either LAST or CAT was significantly higher in subjects with rosacea (p < 0.001), but not in that with seborrheic dermatitis. Similarly, individuals with rosacea displayed a higher positive rate to both LAST and CAT than those with seborrheic dermatitis and normal controls (p < 0.001). In parallel, the LAST scores and CAT scores in individuals with rosacea were significantly higher than in that with either seborrheic dermatitis or normal controls (p < 0.001). The baseline TEWL rates and erythema indexes were higher in individual with rosacea than in normal controls (p < 0.001). But the baseline TEWL rates and erythema indexes did not differ significantly between subjects with rosacea and that with seborrheic dermatitis. Moreover, LAST scores and CAT scores correlated positively with TEWL (p < 0.0001). TEWL rates were higher in CAT positive than in CAT negative subjects (p < 0.0001). Finally, erythema index correlated positively with CAT scores (p < 0.0001), but not with LAST scores (p = 0.0842). Skin responses to LAST and CAT differ between individuals with rosacea and those with seborrheic dermatitis, possibly due to the differences in epidermal permeability barrier and the neurovascular hyperreactivity. The higher LAST and CAT scores, as well as positive rates of both LAST and CAT can be attributable to inferior permeability barrier and the neurovascular hyperreactivity in subjects with rosacea.

Topical emollient prevents the development of atopic dermatitis and atopic march in mice.

To investigate the effect of emollient on atopic march in a murine model of atopic dermatitis (AD). Following induction of AD with topical calcipotriol (MC903) and ovalbumin (OVA), one group of mice was treated topically with a linoleic acid-ceramide-containing emollient, while mice without emollient treatment served as disease controls. After 28 days, clinical, histological and transcriptomic analyses were performed in the skin lesions and the lung as well as serum cytokine levels. Treatments of mice with MC903 and OVA induced a typical phenotype of AD, accompanied by increased expression levels of Th2 and basophil-related genes in the lung. Topical emollients markedly decreased the severity of skin lesions and inflammatory cell infiltration. Moreover, emollient treatments significantly downregulated expression levels of AD-related genes (286 of 1450 differentially expressed genes), including those related to innate inflammation (S100a8/a9, Il1b, Defb3/6, Mmp12), chemokines (Cxcl1/3, Ccl3/4) and epidermal permeability barrier (Krt2/6b/80, Serpinb12, Lce3e, Sprr2), etc. Downregulated genes were enriched in mitochondrial OXPHOS-related pathways, while upregulated genes were mainly enriched in axon guidance and tight junctions. Moreover, topical emollient treatments decreased total serum levels of IL-4, along with substantial reductions in IgE and thymic stromal lymphopoietin (TSLP) levels. Furthermore, 187 of 275 upregulated genes in lung tissue were also significantly downregulated, including those involved in leucocyte chemotaxis (Ccl9, Ccr2, Retnlg, Ccl3, Cxcl10, Il1r2, etc.) and basophil activation (Mcpt8, Cd200r3, Fcer1a, Ms4a2). In conclusion, topical emollient not only reduces skin inflammation, but also mitigates systemic inflammation by decreasing TSLP and IgE levels. Moreover, topical emollient reduces chemokine production and basophil infiltration and activation in the lung.

Ligand Activation of the Aryl Hydrocarbon Receptor Upregulates Epidermal Uridine Diphosphate Glucose Ceramide Glucosyltransferase and Glucosylceramides

Ligand activation of the aryl hydrocarbon receptor (AHR) accelerates keratinocyte differentiation and the formation of the epidermal permeability barrier. Several classes of lipids, including ceramides, are critical to the epidermal permeability barrier. In normal human epidermal keratinocytes, the AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, increased RNA levels of ceramide metabolism and transport genes: uridine diphosphate glucose ceramide glucosyltransferase (UGCG), ABCA12, GBA1, and SMPD1. Levels ofabundant skin ceramides were also increased by 2,3,7,8-tetrachlorodibenzo-p-dioxin. These included themetabolites synthesized by UGCG, glucosylceramides, and acyl glucosylceramides. Chromatin immunoprecipitation-sequence analysis and luciferase reporter assays identified UGCG as a direct AHR target. The AHR antagonist, GNF351, inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated RNA and transcriptional increases. Tapinarof, an AHR ligand approved for the treatment of psoriasis, increased UGCG RNA, protein, and its lipid metabolites hexosylceramides as well as increased the RNA expression of ABCA12, GBA1, and SMPD1. In Ahr-null mice, Ugcg RNA and hexosylceramides were lower than those in the wild type. These results indicate that the AHR regulates the expression of UGCG, a ceramide-metabolizing enzyme required for ceramide trafficking, keratinocyte differentiation, and epidermal permeability barrier formation.

Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies

Self-healing collodion baby (SHCB), also called “self-improving collodion baby”, is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

Poria cocos Extract from Mushrooms Stimulates Aquaporin-3 via the PI3K/Akt/mTOR Signaling Pathway.

BackgroundPoria cocos (PC), a fungus, has been used for more than 2000 years as a food and medicine in China. PC and its components have various pharmacological effects on the skin, including immunomodulatory activities, barrier function improvement, and anti-tumor effects. However, the effect of PC in aquaporin-3 (AQP3) expression, which is essential for epidermal water permeability barrier maintenance, was not reported.MethodsThis study examined the mechanism through which the ethanol extract of the sclerotium of PC (EPC) promoted the expression of AQP3 in cultured human keratinocytes. Western blotting was used to investigate the expression of AQPs and the activation of phosphoinositide 3-kinase (PI3K)/Akt-related signaling molecules in HaCaT cells. Cells were treated with inhibitors of PI3K/Akt and mechanistic target of rapamycin (mTOR) prior to EPC treatment.ResultsEPC promoted the expression of AQP3 in HaCaT cells without affecting AQP1 and AQP2 expression. Phosphorylated Akt levels were increased by EPC treatment, and the inhibition of PI3K by LY2940002 resulted in a reduction in EPC-induced AQP3 expression. Furthermore, EPC stimulated the phosphorylation of p70S6K and AktSer473, which are downstream targets of mTORC1 and mTORC2, respectively. The mTOR complex inhibitors, rapamycin and Torin 1, partially reduced EPC-induced AQP3 expression.ConclusionThese results suggest that EPC increased expression of AQP3, which is important for skin moisturization, by activating the PI3K/Akt/mTOR signaling pathway in human keratinocytes.

PNPLA1-Mediated Acylceramide Biosynthesis and Autosomal Recessive Congenital Ichthyosis.

The stratum corneum of the epidermis acts as a life-sustaining permeability barrier. Unique heterogeneous ceramides, especially ω-O-acylceramides, are key components for the formation of stable lamellar membrane structures in the stratum corneum and are essential for a vital epidermal permeability barrier. Several enzymes involved in acylceramide synthesis have been demonstrated to be associated with ichthyosis. The function of patatin-like phospholipase domain-containing protein 1 (PNPLA1) was a mystery until the finding that PNPLA1 gene mutations were involved in autosomal-recessive congenital ichthyosis (ARCI) patients, both humans and dogs. PNPLA1 plays an essential role in the biosynthesis of acylceramide as a CoA-independent transacylase. PNPLA1 gene mutations cause decreased acylceramide levels and impaired skin barrier function. More and more mutations in PNPLA1 genes have been identified in recent years. Herein, we describe the structural and functional specificity of PNPLA1, highlight its critical roles in acylceramide synthesis and skin barrier maintenance, and summarize the PNPLA1 mutations currently identified in ARCI patients.

587 A formulation containing extracts of two herbs and two algae is a clean, green alternative for multiple ingredients used in topical therapeutic products

A novel mixture of peptide dominant extracts of Acacia and Maca herbs with Chlorella and Clamydomonas algae provide several of the desired functionalities for ingredients in topical formulations for skin care and therapeutic products. A 10 subject randomized in vivo trial compared this herbal/algal test formulation containing these four extracts of repairing of the epidermal permeability barrier after tape stripping. Then after a single application at four different sites of the test formulation(TF), 100% petrolatum(P) and 100% mineral oil(MO), Tewameter measurements were taken at 4 time points between 20 minutes and 6 hours.

Small, Cationic Antifungal Proteins from Filamentous Fungi Inhibit Candida albicans Growth in 3D Skin Infection Models.

ABSTRACTThe emerging resistance of human-pathogenic fungi to antifungal drugs urges the development of alternative therapeutic strategies. The small, cationic antifungal proteins (AFPs) from filamentous ascomycetes represent promising candidates for next-generation antifungals. These bio-molecules need to be tested for tolerance in the host and efficacy against fungal pathogens before they can be safely applied in humans. Testing of the efficacy and possible adverse effects of new drug candidates in three-dimensional (3D) human-cell based models represents an advantageous alternative to animal experiments. In, this study, as a proof-of-principle, we demonstrate the usefulness of 3D skin infection models for screening new antifungal drug candidates for topical application. We established a cutaneous infection with the opportunistic human-pathogenic yeast Candida albicans in a commercially available 3D full-thickness (FT) skin model to test the curative potential of distinct AFPs from Penicillium chrysogenum (PAFopt, PAFB, and PAFC) and Neosartorya (Aspergillus) fischeri (NFAP2) in vitro. All tested AFPs were comparably well tolerated by the skin models. The infected 3D models exhibited reduced epidermal permeability barriers, allowing C. albicans to colonize the epidermal and dermal layers, and showed increased secretion of the pro-inflammatory cytokine IL-6 and the chemokine IL-8. AFP treatment diminished the fungal burden and penetration depth of C. albicans in the infected models. The epidermal permeability barrier was restored and the secretion of IL-8 was decreased following AFP treatment. In summary, our study proves that the tested AFPs exhibit antifungal potential against cutaneous C. albicans infection in a 3D FT skin model.IMPORTANCE Candida albicans represents one of the most prevalent opportunistic fungal pathogens, causing superficial skin and mucosal infections in humans with certain predisposing health conditions and life-threatening systemic infections in immunosuppressed patients. The emerging drug resistance of this human-pathogenic yeast and the limited number of antifungal drugs for prevention and treatment of infections urgently demands the identification of new antifungal compounds with novel mechanisms of action. Small, cationic antifungal proteins (AFPs) from filamentous fungi represent promising candidates for next-generation antifungals for topical application. These bio-molecules need to be tested for tolerance by the host and efficacy in pathogen clearance prior to being involved in clinical trials. In a proof-of-principle study, we provide evidence for the suitability of 3D human-cell based models as advantageous alternatives to animal experiments. We document the tolerance of specific AFPs and their curative efficacy against cutaneous C. albicans infection in a 3D skin model.

Optimised emollient mixture for skin barrier repair: Applications to global child health.

INTRODUCTION: IMPORTANCE OF SKIN BARRIER HOMEOSTASIS Maintenance of epidermal permeability barrier homeostasis is required for life in a desiccating, often hostile, terrestrial environment. Children over six months of age and adults who are armed with robust metabolic machinery readily cope with most external stressors [1]. In contrast, individuals with sub-optimal permeability barriers – including the […]

Impacts of sun protection and skin care habits in the biophysical and morphological properties of young men skin.

Previous studies have demonstrated that UVB radiation may cause changes in the epidermal permeability barrier and in the stratum corneum hydration. It is also well known that sun exposure causes erythema, skin cancer, and other physiologic alterations. Furthermore, because of the cultural barrier, men usually apply less sunscreen. The objective of this study was to evaluate the cosmetic use and sun protection habits of young men, correlating their lifestyle with the biophysical and morphological skin characteristics, as well as to study how skin unprotected sun exposure can affect these features even in young people. 60 participants between 18 and 28years old were divided into two groups: with photoprotection habits (PP habits) and without photoprotection habits (No PP habits). They were questioned about their sunscreen and cosmetic products use. The skin parameters were evaluated using biophysical and skin imaging techniques. 60% of the participants did not apply sunscreen often, and 80% did not consume other skin care products. No PP habits group presented an increase in the transepidermal water loss-TEWL and sebum level, as well as a reduction in the stratum corneum water content and dermis echogenicity. The skin characteristics evaluated in this study were correlated with the sun protection habits and skin care behavior showing that men face some sociocultural barrier to start the use of cosmetic products. Thus, it is important to consider this information for the dermatological clinical and development of cosmetic products for men's skin.

Secretory leukocyte protease inhibitor regulates nerve reflex-mediated skin barrier function in psoriasis.

BackgroundSecretory leukocyte protease inhibitor (SLPI), a ~12 kDa protein is an important regulator of innate and adaptive immunity and a component of tissue regenerative programmes. SLPI expression is markedly elevated in chronically inflamed skin, including that of individuals suffering from psoriasis. However, the role of SLPI in these diseases remains elusive.ObjectivesThe poor understanding of the early stages of the development of psoriasis is a major obstacle to successful intervention in the skin pathology. We hypothesized that SLPI and peripheral nerves that might be activated early in the progression of the disease likely form a functional relationship to maintain skin barrier homeostasis and respond to a variety of threats.MethodsWe used skin biopsies of healthy donors and individuals with psoriasis to show expression pattern of SLPI. A role of SLPI in psoriasis was mechanistically assessed using SLPI‐deficient mice and an imiquimod (IMQ)‐induced experimental model of psoriasis.ResultsWe show that mice lacking SLPI had exaggerated skin alterations that extended beyond the treatment site in an imiquimod‐induced psoriasis. The spatiotemporally distinct skin responses in SLPI‐deficient mice, compared to their wild‐type littermates, resulted from a compromised skin barrier function that manifested itself in heightened transepidermal water loss through the larger skin area surrounding the IMQ‐challenged skin. The increased pathogenic skin changes in the absence of SLPI were reversible through pharmacological treatment that blocks a nerve‐reflex arc.ConclusionsTogether, these data indicate that SLPI plays a protective role in psoriasis through preventing skin dryness, inherent in the pathogenesis of psoriasis and that this SLPI action depends on neuronal input operating in a reflex manner. These findings reveal a previously unrecognized mechanism that maintains cutaneous homeostasis, which involves a crosstalk between the nervous system and a protein anatomically poised to fortify the epidermal permeability barrier.

Keratin 17 Is Required for Lipid Metabolism in Keratinocytes and Benefits Epidermal Permeability Barrier Homeostasis.

The epidermal barrier refers to the stratum corneum, the uppermost layer of the skin, and constitutes the first line of defense against invasion by potentially harmful pathogens, diminishes trans-epidermal water loss, and plays a crucial role in the maintenance of skin homeostasis. Keratin 17 (K17) is a type I epithelial keratin with multiple functions, including in skin inflammation, epithelial cell growth, protein synthesis, and tumorigenesis. However, the relationship between K17 and the skin barrier has yet to be systematically investigated. In this study, we found that acute disruption of the epidermal permeability barrier led to a rapid increase in epidermal K17 expression in vivo. Krt17 gene deficiency in mice resulted in decreased expression of lipid metabolism-related enzymes and antimicrobial peptides, while also delaying epidermal permeability barrier recovery after acute disruption. Adenovirus-mediated overexpression of K17 enhanced, whereas siRNA-mediated knockdown of Krt17 inhibited, the expression of fatty acid synthase (FASN) and that of the transcription factors SREBP-1 and PPARγ in vitro. We further confirmed that K17 can facilitate the nuclear transportation of SREBP-1 and PPARγ and promote lipid synthesis in keratinocytes. This study demonstrated that K17 contributes to the restoration of the epidermal permeability barrier via stabilizing lipid metabolism in keratinocytes.

CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers.

Claudins (CLDNs) are the most important tight junction proteins, which are mainly expressed in endothelial cells or epithelial cells in a tissue-specific manner. As a member of the CLDNs family, CLDN6 is highly expressed in fetal tissues such as the stomach, pancreas, lung, and kidney, but is not expressed in corresponding adult tissues. The expression of CLDN6 is regulated by a variety of factors, including but not limited to stimuli and transcription factors, DNA methylation, and post-translational modifications. CLDN6 has been found to have a key role in the formation of barriers, especially the lung epithelial barrier and the epidermal permeability barrier (EPB). Importantly, the roles of CLDN6 in cancers have gained focus and are being investigated in recent years. Strong evidence indicates that the altered expression of CLDN6 is linked to the development of various cancers. Malignant phenotypes of tumors affected by CLDN6 include proliferation and apoptosis, migration and invasion, and drug resistance, which are regulated by CLDN6-mediated key signaling pathways. Given the important role in tumors and its low or no expression in normal tissues, CLDN6 is an ideal target for tumor therapy. This review aims to provide an overview of the structure and regulation of CLDN6, and its traditional barrier function, with a special emphasis on its emerging roles in cancers, including its impact on the malignant phenotypes, signal-modulating effects, the prognosis of tumor patients, and clinical applications in cancers.