Epidermal Barrier Research Articles

Identification of Key Genes Related to Immune-Lipid Metabolism in Skin Barrier Damage and Analysis of Immune Infiltration.

Several physical and chemical factors regulate skin barrier function. Skin barrier dysfunction causes many inflammatory skin diseases, such as atopic dermatitis and psoriasis. Activation of the immune response may lead to damage to the epidermal barrier. Abnormal lipid metabolism is defined as abnormally high or low values of plasma lipid components such as plasma cholesterol and triglycerides. The mouse skin barrier damage model was used for RNA sequencing. Bioinformatics analysis and validation were performed. Differently expressed genes (DEGs) related to immune and lipid metabolism were screened by differentially expressed gene analysis, and the enriched biological processes and pathways of these genes were identified by GO-KEGG. The interactions between DEGs were confirmed by constructing a PPI network. GSEA, transcription factor regulatory network, and immune infiltration analyses were performed for the 10 genes. Expression validation was performed by public datasets. The expression of key genes in mouse skin tissue was detected by qPCR. The expression of differentially expressed immune cell markers in the skin was detected by immunofluorescence. Based on the trans epidermal water loss (TEWL) score, the expression of key genes was detected by qPCR before skin barrier injury, at 4h and 7d, and at recovery from injury. Il17a, Il6, Tnf, Itgam, and Cxcl1 were immune-related key genes. Pla2g2f, Ptgs2, Plb1, Pla2g3, and Pla2g2d were key genes for lipid metabolism. Database validation and experimental results revealed that the expression trends of these genes were consistent with our analyses. The research value of these genes has been demonstrated through mouse datasets and experimental validation, and future therapeutic approaches may be able to mitigate the disease by targeting these genes to modulate the function of the skin barrier.

Activation of the aryl hydrocarbon receptor via indole derivatives is a common feature in skin bacterial isolates.

The aryl hydrocarbon receptor (AhR) is a ligand-activated receptor implicated in many inflammatory disorders. The skin microbiota plays a crucial role in maintaining epidermal barrier integrity and is thought to modulate skin homeostasis partly through the production of AhR ligands including metabolites of microbial tryptophan metabolism such as indole derivatives. Here, we report the skin microbiota that activate AhR and their unique tryptophan metabolite profiles. Of the bacteria isolated from healthy human skin and screened for the ability to metabolise tryptophan (18 species, five genera), 14 were positive. The tryptophan metabolites of 10 positive and two negative bacteria were then characterised using liquid chromatography-mass spectrometry. Whole genome sequencing confirmed the presence of key genes involved in the indole-3-pyruvic acid pathway within the genomes of indole-3-acetaldehyde, indole-3-acetic acid, and indole-3-aldehyde-producing organisms. A cell-based luciferase reporter gene assay identified functional agonist activity against human AhR in the culture supernatants of 12 of the 18 species tested. High indole derivative-producing organisms induced potent AhR activation. These data demonstrate the relationship between skin microbiota, tryptophan metabolites, and AhR activation.

NLRP10 maintains epidermal homeostasis by promoting keratinocyte survival and P63-dependent differentiation and barrier function

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by disrupted epidermal barrier function and aberrant immune responses. Despite recent developments in new therapeutics for AD, there is still a large unmet medical need for disease management due to the complex and multifactorial nature of AD. Recent genome-wide association studies (GWAS) have identified NLRP10 as a susceptible gene for AD but the physiological role of NLRP10 in skin homeostasis and AD remains unknown. Here we show that NLRP10 is downregulated in AD skin samples. Using an air-lift human skin equivalent culture, we demonstrate that NLRP10 promotes keratinocyte survival and is required for epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of caspase-8 to the death inducing signaling complex (DISC) and by inhibiting its subsequent activation. NLRP10 also stabilizes p63, the master regulator of keratinocyte differentiation, to drive proper keratinocyte differentiation and to reinforce the barrier function. Our findings underscore NLRP10 as a key player in atopic dermatitis pathogenesis, highlighting NLRP10 as a potential target for therapeutic intervention to restore skin barrier function and homeostasis in AD.

A sphingolipid rheostat controls apoptosis versus apical cell extrusion as alternative tumour-suppressive mechanisms

Evasion of cell death is a hallmark of cancer, and consequently the induction of cell death is a common strategy in cancer treatment. However, the molecular mechanisms regulating different types of cell death are poorly understood. We have formerly shown that in the epidermis of hypomorphic zebrafish hai1a mutant embryos, pre-neoplastic transformations of keratinocytes caused by unrestrained activity of the type II transmembrane serine protease Matriptase-1 heal spontaneously. This healing is driven by Matriptase-dependent increased sphingosine kinase (SphK) activity and sphingosine-1-phosphate (S1P)-mediated keratinocyte loss via apical cell extrusion. In contrast, amorphic hai1afr26 mutants with even higher Matriptase-1 and SphK activity die within a few days. Here we show that this lethality is not due to epidermal carcinogenesis, but to aberrant tp53-independent apoptosis of keratinocytes caused by increased levels of pro-apoptotic C16 ceramides, sphingolipid counterparts to S1P within the sphingolipid rheostat, which severely compromises the epidermal barrier. Mathematical modelling of sphingolipid rheostat homeostasis, combined with in vivo manipulations of components of the rheostat or the ceramide de novo synthesis pathway, indicate that this unexpected overproduction of ceramides is caused by a negative feedback loop sensing ceramide levels and controlling ceramide replenishment via de novo synthesis. Therefore, despite their initial decrease due to increased conversion to S1P, ceramides eventually reach cell death-inducing levels, making transformed pre-neoplastic keratinocytes die even before they are extruded, thereby abrogating the normally barrier-preserving mode of apical live cell extrusion. Our results offer an in vivo perspective of the dynamics of sphingolipid homeostasis and its relevance for epithelial cell survival versus cell death, linking apical cell extrusion and apoptosis. Implications for human carcinomas and their treatments are discussed.

Epidermal RORα Maintains Barrier Integrity and Prevents Allergic Inflammation by Regulating Late Differentiation and Lipid Metabolism.

The skin epidermis provides a barrier that is imperative for preventing transepidermal water loss (TEWL) and protecting against environmental stimuli. The underlying molecular mechanisms for regulating barrier functions and sustaining its integrity remain unclear. RORα is a nuclear receptor highly expressed in the epidermis of normal skin. Clinical studies showed that the epidermal RORα expression is significantly reduced in the lesions of multiple inflammatory skin diseases. In this study, we investigate the central roles of RORα in stabilizing skin barrier function using mice with an epidermis-specific Rora gene deletion (RoraEKO). While lacking spontaneous skin lesions or dermatitis, RoraEKO mice exhibited an elevated TEWL rate and skin characteristics of barrier dysfunction. Immunostaining and Western blot analysis revealed low levels of cornified envelope proteins in the RoraEKO epidermis, suggesting disturbed late epidermal differentiation. In addition, an RNA-seq analysis showed the altered expression of genes related to "keratinization" and "lipid metabolism" in RORα deficient epidermis. A lipidomic analysis further uncovered an aberrant ceramide composition in the RoraEKO epidermis. Importantly, epidermal Rora ablation greatly exaggerated percutaneous allergic inflammatory responses to oxazolone in an allergic contact dermatitis (ACD) mouse model. Our results substantiate the essence of epidermal RORα in maintaining late keratinocyte differentiation and normal barrier function while suppressing cutaneous inflammation.

OBP2A regulates epidermal barrier function and protects against cytotoxic small hydrophobic molecules

OBP2A regulates epidermal barrier function and protects against cytotoxic small hydrophobic molecules

Pharmacological Impacts of Mucopolysacccharide Polyphosphates in the Epidermis Involves Inhibition of Amphiregulin-Mediated Signals in Keratinocytes.

The epidermis, the most superficial layer of the human skin, serves a critical barrier function, protecting the body from external pathogens and allergens. Dysregulation of epidermal differentiation contributes to barrier dysfunction and has been implicated in the pathology of various dermatological diseases, including atopic dermatitis (AD). Mucopolysaccharide polysulphate (MPS) is a moisturising agent used to treat xerosis in patients with AD. However, its mechanism of action on keratinocytes, the main constituents of the epidermis, remains unclear. In this study, we investigated the effect of MPS on keratinocytes by subjecting adult human epidermal and three-dimensional cultured keratinocytes to MPS treatment, followed by transcriptome analysis. The analysis revealed that MPS treatment enhances keratinocyte differentiation and suppresses proliferation. We focused on amphiregulin (AREG), a membrane protein that belongs to the epidermal growth factor (EGF) family and possesses a heparin-binding domain, as a significant target among the genes altered by MPS. MPS exerted an inhibitory effect directly on AREG, rather than on EGF receptors or other members of the EGF family. Furthermore, AREG leads to a reduction in epidermal barrier function, whereas MPS contributes to barrier enhancement via AREG inhibition. Collectively, these findings suggest that MPS modulates barrier function through AREG inhibition, offering insights into potential therapeutic strategies for skin barrier restoration.

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. Crosslinking assays of recombinant LCE6A performed either insitu on human skin sections or invitro demonstrated that LCE6A is indeed a substrate of transglutaminases and crosslinked to CEs. LCE6A-derived peptides containing a glutamine-lysine sequence retained these properties of the full-length protein and reinforced the mechanical resistance of CE submitted to sonication. We designed P26, a LCE6A-derived biomimetic peptide that similarly reinforced CE invitro, and evaluated its protective properties exvivo, on human skin explants, and in two double blind and vehicle-controlled clinical trials. P26 was able to protect the skin from barrier disruption, to limit the damage resulting from a defective barrier, and could improve the signs of aging such as loss of skin firmness and increased skin roughness. Hence, our detailed characterisation of LCE6A as a component of the CE enabled us to develop a LCE6A-derived peptide, biologically active with a new and original mode of action that could be of great interest as a cosmetic ingredient and a pharmacologic agent.

Nrf2 Activation in Keratinocytes: A Central Role in Diabetes-Associated Wound Healing.

Wound healing is a complex biological process crucial for tissue repair, wherein keratinocytes play a pivotal role in initiating, sustaining and completing the cascade. Various local and systemic factors, such as lifestyle, age metabolic disorders and vascular insufficiency, can influence this process, and in the context of diabetic wounds, disrupted biological mechanisms, including inflammation, tissue hypoxia, decrease in collagen production along with increased oxidative stress and keratinocyte dysfunction, contribute to delayed healing. During re-epithelialisation, keratinocytes undergo rapid multiplication and migration, forming a dense hyperproliferative epithelial layer that restores the epidermal barrier. Nuclear factor-erythroid 2-related factor (Nrf2), a vital transcription factor, emerges as a central regulator in managing antioxidant proteins and detoxifying enzymes, serving as a guardian against elevated reactive oxygen species (ROS) levels during stress. Nrf2 also orchestrates angiogenesis and anti-inflammatory responses crucial for wound repair. Studies demonstrate that under high-glucose conditions, Nrf2 activation promotes wound healing by enhancing cell proliferation and migration while reducing apoptosis. Nrf2 activators stimulate endogenous antioxidant production, thereby mitigating oxidative stress. Furthermore, Nrf2 upregulation is associated with decreased expression of cytokines such as TNF-α and IL- 6. Recent research underscores the potential of bioactive molecules, including dietary polyphenols, traditional medicinal compounds and pharmacological agents, in activating Nrf2 and preventing diseases such as diabetes due to their robust antioxidative properties. This review aims to investigate the activation of Nrf2 by these bioactive molecules in cultured keratinocytes and animal models, elucidating the key molecular regulatory mechanisms involved in alleviating oxidative stress and facilitating the diabetic wound healing process. Understanding these complex pathways may offer insights into novel therapeutic strategies for enhanced wound healing in diabetes-associated complications.

Implications of the non-neuronal cholinergic system for therapeutic interventions of inflammatory skin diseases.

The pivotal roles of acetylcholine (ACh) in physiological processes encompass both the nervous and non-neuronal cholinergic systems (NNCS). This review delineates the synthesis, release, receptor interactions, and degradation of ACh within the nervous system, and explores the NNCS in depth within skin cells including keratinocytes, endothelial cells, fibroblasts, macrophages, and other immune cells. We highlight the NNCS's essential functions in maintaining epidermal barrier integrity, promoting wound healing, regulating microcirculation, and modulating inflammatory responses. The potential of the NNCS as a therapeutic target for localized ACh regulation in the skin is discussed, though the translation of these findings into clinical practice remains uncertain due to the complexity of cholinergic signalling and the lack of comprehensive human studies. The review progresses to therapeutic modulation strategies of the NNCS, including AChE inhibitors, nicotinic and muscarinic receptor agonists and antagonists, choline uptake enhancers, and botulinum toxin, highlighting their relevance in dermatology. We highlight the impact of the NNCS on prevalent skin diseases such as psoriasis, atopic dermatitis, rosacea, acne, bullous diseases, hyperhidrosis and hypohidrosis, illustrating its significance in disease pathogenesis and therapy. This comprehensive overview aims to enhance understanding of the NNCS's role in skin health and disease, offering a foundation for future research and therapeutic innovation.

Recombinant filaggrin-2 improves skin barrier function and attenuates ultraviolet B (UVB) irradiation-induced epidermal barrier disruption

The integrity of the skin barrier is essential for maintaining skin health, with the stratum corneum and filaggrin 2 (FLG-2) playing a key role. FLG-2 deficiency or mutation has been linked to diseases such as atopic dermatitis, while external stressors such as ultraviolet B (UVB) radiation further damage the epidermal barrier. This study investigated the effects of recombinant filaggrin (rFLG) on skin barrier function and UVB induced epidermal destruction. Cell experiments showed that 10 μg/mL of rFLG could increase the mobility of HaCaT cells from 20 % to 42 %, increase the epithelial resistance (TEER) value by about 2 times, and up-regulate the tight junction associated protein by about 2 times. In mouse models of UVB-induced epidermal barrier destruction, rFLG at concentrations of 0.5, 1, and 2 mg/mL showed effective cell uptake and skin penetration, alleviating erythema, and reducing skin thickness in mice by 1.5–3 times. Among them, 2 mg/mL of rFLG treatment restored the expression of tight junction proteins (LOR, ZO-1, and caspase-14), reduced collagen degradation, and reduced oxidative stress by normalizing serum hydroxyproline and superoxide dismutase levels. In addition, 2 mg/mL of rFLG inhibited UVB-induced upregulation of matrix metalloproteinases (MMP-3 and MMP-9) and reduced pro-inflammatory factors (IL-10, IL-1α, IL-6, and TNF-α) and apoptotic markers (P38, Bax, and Bcl-2) to normal levels. These findings suggested that rFLG effectively enhanced skin barrier integrity and mitigated UVB-induced epidermal barrier destruction, highlighting its potential as a therapeutic agent for diseases associated with skin barrier dysfunction.

Benefits of natural edible ingredients in epidermal permeability barrier function.

Benefits of natural edible ingredients in epidermal permeability barrier function.

Effect of Staphylococcus aureus colonization and immune defects on the pathogenesis of atopic dermatitis.

Atopic dermatitis (AD) is a common and recurrent skin disease characterized by skin barrier dysfunction, inflammation and chronic pruritus, with wide heterogeneity in terms of age of onset, clinical course and persistence over the lifespan. Although the pathogenesis of the disease are unclear, epidermal barrier dysfunction, immune and microbial dysregulation, and environmental factors are known to be critical etiologies in AD pathology. The skin microbiota represents an ecosystem consisting of numerous microbial species that interact with each other as well as host epithelial cells and immune cells. Although the skin microbiota benefits the host by supporting the basic functions of the skin and preventing the colonization of pathogens, disruption of the microbial balance (dysbiosis) can cause skin diseases such as AD. Although AD is a dermatological disease, recent evidence has shown that changes in microbiota composition in the skin and intestine contribute to the pathogenesis of AD. Environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, diet, irritants, air pollution, epigenetics and microbial exposure. Knowing the microbial combination of intestin, as well as the genetic and epigenetic determinants associated with the development of autoantibodies, may help elucidate the pathophysiology of the disease. The skin of patients with AD is characterized by microbial dysbiosis as a result of reduced microbial diversity and overgrowth of the pathogens such as Staphylococcus aureus. Recent studies have revealed the importance of building a strong immune response against microorganisms during childhood and new mechanisms of microbial community dynamics in modulating the skin microbiome. Numerous microorganisms are reported to modulate host response through communication with keratinocytes, specific immune cells and adipocytes to improve skin health and barrier function. This growing insight into bioactive substances in the skin microbiota has led to novel biotherapeutic approaches targeting the skin surface for the treatment of AD. This review will provide an updated overview of the skin microbiota in AD and its complex interaction with immune response mechanisms, as well as explore possible underlying mechanisms in the pathogenesis of AD and provide insights into new therapeutic developments for the treatment of AD. It also focuses on restoring skin microbial homeostasis, aiming to reduce inflammation by repairing the skin barrier.

The Impact of Air Pollution on Atopic Dermatitis. Literature review

Introduction and purpose The rising level of air pollution is currently a serious worldwide problem. Airborne pollutants, such as PM, O3, CO, NOx, SO₂, and heavy metals, negatively impact the entire body, contributing to the dysfunction of many systems. The aim of this study was to review the literature on the impact of selected air pollutants on the development or exacerbation of atopic dermatitis, and to elucidate the mechanisms responsible for this. Materials and methods The literature available in PubMed and Google Scholar databases was reviewed using the keywords: “air pollution”, “atopic dermatitis”, “skin lesions”. Description of the state of knowledge Available studies have provided information on the significant impact of air pollution on the development and exacerbation of atopic dermatitis. Air pollutants can induce skin changes through various mechanisms, such as damage to the epidermal barrier, disruption of skin microflora, oxidative stress, initiation of inflammatory responses, or activation of the aryl hydrocarbon receptor pathway. Conclusions Reducing air pollution is crucial for improving overall public health and decreasing the incidence of many diseases, including atopic dermatitis. Further research is needed to deepen the understanding of the relationship between air pollution and atopic dermatitis, as well as the mechanisms responsible for it, and to develop effective strategies for protecting the skin from pollutants.

Neutrophils in Atopic Dermatitis.

Neutrophils have a critical role in inflammation. Recent studies have identified their distinctive presence in certain types of atopic dermatitis (AD), yet their exact function remains unclear. This review aims to compile studies elucidating the role of neutrophils in AD pathophysiology. Proteins released by neutrophils, including myeloperoxidase, elastase, and lipocalin, contribute to pruritus progression in AD. Neutrophilic oxidative stress and the formation of neutrophil extracellular traps may further worsen AD. Elevated neutrophil elastase and high-mobility group box 1 protein expression in AD patients' skin exacerbates epidermal barrier defects. Neutrophil-mast cell interactions in allergic inflammation steer the immunological response toward Th2 imbalance and activate the Th17 pathway, particularly in response to allergens or infections linked to AD. Notably, drugs alleviating pruritic symptoms in AD inhibit neutrophilic inflammation. In conclusion, these findings underscore that neutrophils may be therapeutic targets for AD symptoms, emphasizing their inclusion in AD treatment strategies.

The role of the skin in the atopic march.

Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called 'atopy') and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred as the 'atopic march' (AM). Clinical, genetic and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM, to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.

Anti-ageing mechanism of topical bioactive ingredient composition on skin based on network pharmacology.

To elucidate the anti-ageing mechanism of the combination of eight ingredients on the skin from a multidimensional view of the skin. The target pathway mechanisms of composition to delay skin ageing were investigated by a network pharmacology approach and experimentally validated at three levels: epidermal, dermal, and tissue. We identified 24 statistically significant skin ageing-related pathways, encompassing crucial processes such as epidermal barrier repair, dermal collagen and elastin production, inhibition of reactive oxygen species (ROS), as well as modulation of acetylcholine and acetylcholine receptor binding. Furthermore, our invitro experimental findings exhibited the following outcomes: the composition promotes fibroblast proliferation and the expression of barrier-related genes in the epidermis; it also stimulated the expression of collagen I, collagen III, and elastic fibre while inhibiting ROS and β-Gal levels in HDF cells within the dermis. Additionally, Spilanthol in the Acmella oleracea extract contained in the composition demonstrated neuro-relaxing activity in Zebrafish embryo, suggesting its potential as an anti-wrinkle ingredient at the hypodermis level. In vitro experiments validated the anti-ageing mechanism of composition at multiple skin levels. This framework can be extended to unravel the functional mechanisms of other clinically validated compositions, including traditional folk recipes utilized in cosmeceuticals.

The Effect of Polynucleotide‐Hyaluronic Acid Hydrogel in the Recovery After Mechanical Skin Barrier Disruption

ABSTRACTBackgroundThe epidermal barrier acts as a defense against external agents as well as helps to maintain body homeostasis. Polynucleotides (PN), exogenous DNA fragments, promote wound repair through their stimulatory and anti‐inflammatory effects. Recent findings indicate a synergistic effect of PN and hyaluronic acid (HA) combinations in regulating inflammation and promoting cell proliferation. This study aims to elucidate the effects of PN and HA on repairing the epidermal barrier following its disruption by tape stripping (TS) in a mouse model.Materials and MethodsAfter disrupting the epidermal barrier using TS, a formulation containing PN (14 mg/mL) and HA (6 mg/mL) was applied. Trans‐epidermal water loss (TEWL) was measured at 0, 3, 6, 24, 48, and 72 h. Mice were euthanized after the final application at 72 h, and tissue samples were analyzed for epidermal/dermal thickness, neutrophil infiltration, and filaggrin expression.ResultsWe observed a significant reduction in TEWL in the PN+HA group compared to that in the control group (20.8 ± 0.5 vs. 43.7 ± 0.5 g/m2h at 72 h, p < 0.05), indicating an improvement in barrier function. Histological evaluation showed decreased epidermal and dermal thickening in the PN+HA group compared to that in the control group (epidermal: 29.4 ± 2.2 vs. 57.9 ± 3.5 μm; dermal: 464.8 ± 25.9 vs. 825.9 ± 44.8 μm, both p < 0.05). Additionally, neutrophil infiltration in the dermis was significantly reduced, and filaggrin protein levels were significantly higher in the PN+HA group compared to those in the control group (4.8 ± 0.4 vs. 21.1 ± 3.3 for neutrophils; 0.84 ± 0.04 vs. 0.42 ± 0.03 for filaggrin, both p < 0.05).ConclusionThese results suggest that PN+HA may be an effective therapeutic strategy for repairing skin barrier damage.

Understanding the Pathophysiology of Atopic Dermatitis – insights into Immune Dysregulation and Skin Barrier Dysfunction

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disrupted skin barrier and immune dysregulation. The exact pathophysiology of atopic dermatitis despite extensive research remains complex. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, and disruption of the skin’s microbial balance. Recent advances in research have provided deeper insights into the molecular mechanisms including the role of filaggrin mutations, Th2 cytokine-mediated inflammation, and the skin microbiome. Understanding the intricate interplay between these components is crucial for developing targeted therapeutic strategies. Aim of the study: This review provides a comprehensive overview of the current knowledge on the pathophysiological mechanisms underlying AD, highlighting recent advances and areas for future research. Material and methods: Comprehensive literature searches were performed across the main electronic databases of PubMed and GoogleScholar using the keywords: “atopic dermatitis”, “eczema pathophysiology”, “skin barrier”. Conclusions: Atopic dermatitis (AD) is a complex, chronic inflammatory skin disease with a multifaceted pathophysiology involving genetic, immunological, and environmental factors. Recent advances in understanding the molecular mechanisms underlying AD have highlighted the importance of skin barrier dysfunction, immune system dysregulation, and microbial interactions in the disease's progression.

ZnO nanoparticles induce melanoma-like lesions via recruiting dermal dendritic cells in barrier-damaged skin in mice

ZnO nanoparticles (NPs) are used in skin treatments and cosmetics, the toxicity of long-term and continuous exposure to ZnO NPs is unknown. Mice with epidermal barrier dysfunction revealed melanoma-like lesions after continuous exposure to ZnO NPs. However, the effects of metallic NPs on the skin microenvironment and immune system remain poorly understood. Mice with epidermal barrier failure were given continuous exposure to ZnO NPs for 7 weeks. The malignant transformation of melanocytes was induced with ZnO NPs 2.5 μg/ml for 72 h exposure. The supernatant of the culture medium from dendritic cells after being exposed to 10 μg/ml ZnO NPs for 24 h was applied to melanocytes to explore the effect of recruitment of DCs. The expressure of ZnO NPs resulted in a tendency of malignant transformation of melanocytes, the recruitment of DCs induces this process by produce inflammatory factors such as TNF-α. These DC-produced inflammatory factors, which were induced by ZnO NP exposure, increased the production of matrix metalloproteinases in melanocytes and expedited the malignant transformation process. Our findings revealed that the disrupted cutaneous microenvironment by ZnO NPs penetrated directly promoted the malignant transformation of melanocytes, which process also indirectly enhanced by the TNF-αsecreted from the recruited DCs.