Normal Skin Research Articles

Comorbidity Pattern and Autonomic Nervous System Dysfunction in Patients with Chronic Vulvar Discomfort

This study examines novel concepts of comorbidity in patients with chronic vulvar discomfort using data from the DATRIV (Diagnostic Accuracy of Three Rings Vulvoscopy) study, which involved 328 participants categorized into four groups: asymptomatic individuals with normal or impaired vulvar skin and patients with chronic vulvar discomfort, classified as either vulvodynia or vulvar dermatosis. Clinical data were collected through a structured questionnaire and analyzed using statistical software, including StatSoft (Dell, Austin, TX, USA), Statistica 12 (TIBCO®, Palo Alto, CA, USA), and SPSS 20 (IBM, Armonk, NY, USA). The study received approval from the Institutional Review Board of Polyclinic Harni, and all participants provided written informed consent. The findings reveal significantly higher comorbidity rates in patients with chronic vulvar discomfort compared to other groups (p = 0.0000). A substantial percentage of asymptomatic participants with both normal (63.4%) and impaired (70.7%) vulvar skin also reported comorbid conditions. Analysis of comorbidity curves revealed distinct patterns of symptom progression, with a gradual increase in frequency from asymptomatic individuals to patients with vulvodynia, followed by a decline in vulvar dermatosis cases. These patterns highlight the central role of autonomic nervous system (ANS) dysfunction, where sympathetic hyperactivity and parasympathetic depression contribute to separate comorbidity chains. These dysfunctions may act independently or concurrently, leading to various health issues. The elevated comorbidity rates and overlapping symptomatology suggest complex pathophysiology driven by ANS dysregulation. Further research on comorbidity clusters may unveil new therapeutic targets and guide the development of multifaceted treatment strategies.

Perturbations in the skin microbiome of infantile and adult seborrheic dermatitis and new treatment options based on restoring a healthy skin microbiome.

Seborrheic dermatitis (SD) is a common, multifaceted skin condition, but its undefined etiology hampers the development of effective therapeutic strategies. In this review, we describe the intricate relationship between the skin microbiome and the pathogenesis of SD, focusing on the complex interplay between three major groups of organisms that can either induce inflammation (Malassezia spp., Staphylococcus aureus) or else promote healthy skin (Propionibacterium spp.). We describe how the disequilibrium of these microorganisms in the skin microbiome can develop skin inflammation in SD patients. Understanding these complex interactions of the skin microbiome has led to development of novel probiotics (e.g., Vitreoscilla spp. and Lactobacillus spp.) to restore normal skin physiology in SD. There are also differences in the skin microbiomes of healthy and SD infant and adult patients that impact pathogenesis and prompt different management strategies. A deeper understanding of the skin microbiome and its dynamic interactions will provide valuable insights into the pathogenesis of SD and prompt further development of targeted probiotic treatments to restore the balance of the skin microbiome in SD patients.

Automatic construction of Petri net models for computational simulations of molecular interaction network

Petri nets are commonly applied in modeling biological systems. However, construction of a Petri net model for complex biological systems is often time consuming, and requires expertise in the research area, limiting their application. To address this challenge, we developed GINtoSPN, an R package that automates the conversion of multi-omics molecular interaction network extracted from the Global Integrative Network (GIN) into Petri nets in GraphML format. These GraphML files can be directly used for Signaling Petri Net (SPN) simulation. To demonstrate the utility of this tool, we built a Petri net model for neurofibromatosis type I. Simulation of NF1 gene knockout, compared to normal skin fibroblast cells, revealed persistent accumulation of Ras-GTPs as expected. Additionally, we identified several other genes substantially affected by the loss of NF1’s function, exhibiting individual-specific variability. These results highlight the effectiveness of GINtoSPN in streamlining the modeling and simulation of complex biological systems.

Impact of Chronic Moderate Psychological Stress on Skin Aging: Exploratory Clinical Study and Cellular Functioning.

Skin is continuously exposed to environmental external and internal factors, including psychological stress (PS). PS has been reported to trigger different dermatoses such as psoriasis, atopic dermatitis, vitiligo, alopecia areata, and acne through the release of cortisol and epinephrine. To clinically explore PS-induced measurable skin aging signs in subjects with moderate versus mild chronic PS, and to investigate the effect of chronic PS on DNA damage at cellular level. In vitro stress tests with cortisol and epinephrine, and with cortisol only on extracellular matrix (ECM) synthesis, as well as on normal human skin fibroblast and keratinocyte functioning, including skin barrier and wound healing were performed. Moderately stressed subjects in the context of the clinical study had a significantly decreased antioxidant potential and impacted skin barrier integrity, as well as significantly increased signs of microrelief alterations (skin texture and fine lines) reaching an increased severity of about 32.9%. At a cellular level, DNA integrity, ECM synthesis, wound healing, and skin barrier parameters were impacted by increased stress hormone levels. The clinical exploratory studies presented herewith, as well as the study of cell functioning under stress, have provided evidence that chronic PS significantly affects skin homeostasis and triggers skin aging.

Quantifying Mast Cell and Eosinophil Cellular Density in Skin Biopsy Tissue From Adults With Maculopapular Cutaneous Mastocytosis as Compared With Urticaria and Normal Skin: A Retrospective Histopathologic Study.

Maculopapular cutaneous mastocytosis (MPCM) is a rare disorder characterized by a pathologic accumulation of mast cells in the skin, which may or may not be accompanied by systemic mastocytosis. Diagnosis of MPCM on skin biopsy can be challenging because the findings may be subtle. Although mast cell density in MPCM has been reported, data informing a proposed cutoff for diagnosis and diagnostic criteria are limited. We identified adult patients diagnosed with MPCM and urticarial tissue reaction/chronic urticaria on skin biopsy and compared the mast cell and eosinophil counts per 1 mm2 in 10 cases each of MPCM, chronic urticaria, and normal skin from routine biopsies. All slides were stained with CD117, and CD117-positive mast cells were counted per 1 mm2 using digital microscopy. Eosinophils were counted on hematoxylin and eosin-stained slides per 1 mm2 using digital microscopy. The median number of mast cells per 1 mm2 was significantly higher in MPCM than in cases of urticaria and normal skin/control tissue (177.3 vs. 26.8 vs. 47.8 mast cell per mm2, respectively; P ≤ 0.001). The calculated "cut point" for mastocytosis versus chronic urticaria and normal skin was 66 mast cells per 1 mm2, whereas the value for controls versus urticaria was 37 mast cells per 1 mm2. Eosinophils had similar density in MPCM and urticaria, and their presence was significant in the differentiation of MPCM and urticaria from normal tissue. This study adds to the literature by providing objective mast cell density data to distinguish challenging cases of cutaneous mastocytosis from urticarial reactions and normal skin. Future studies could explore the development of computer-aided estimations of cellular density with more extensive comparison with other inflammatory conditions to translate our findings more readily into clinical practice.

Beneficial Effects of Epigallocatechin Gallate in Preventing Skin Photoaging: A Review

Skin photoaging, primarily caused by ultraviolet (UV) radiation, leads to skin metabolic disorders, which have adverse psychological and physiological effects on individuals. However, traditional medications for repairing skin photoaging cause side effects. Natural bioactive compounds have been shown to prevent and treat skin photoaging with fewer side effects. Epigallocatechin gallate (EGCG), the main substance in tea polyphenols, is a natural bioactive compound with a range of properties. This review summarizes the beneficial effects and mechanisms of EGCG, as well as the application forms of EGCG in repairing photoaged skin. Results indicated that EGCG has repair effects, including improving elasticity, enhancing moisturization, inhibiting damage, and reducing pigmentation of photoaged skin. It has also been demonstrated that EGCG delivery systems, modified EGCG, and combinations with other bioactive substances could be used for repairing photoaged skin due to its poor stability and low bioavailability. EGCG effectively repairs various types of skin damage caused by UV radiation while maintaining normal skin structure and function. It is, therefore, an effective candidate for repairing photoaged skin. These results could provide references for the development and application of EGCG products for the treatment of photoaged skin.

Langerhans cells directly interact with resident T cells in the human epidermis

Adult human skin contains nearly twice as many T cells as the peripheral blood, which include tissue-resident memory T (TRM) cells. However, the precise mechanisms maintaining TRM cells in the healthy skin remain unclear. Using normal human skin samples, we find that Langerhans cells (LCs) contact T cells in the epidermis of the elderly. LCs with high human leukocyte antigen (HLA)-II, CD86, and PD-L2 expression directly contacted PD-1+ TRM cells and CTLA-4+ regulatory T cells in the epidermis, indicating an axis of peripheral tolerance in a steady state. Environmental insults, ultraviolet B radiation and hapten, downregulated HLA-II and CD86 on LCs in the epidermis, suggesting that disruption of LC-T cell tolerogenic axis contributes to skin inflammation. Interestingly, immune checkpoint blockade therapy was associated with decreased epidermal LC-T cell contact in the normal skin of cancer patients affected by cutaneous immune-related adverse events. Collectively, our findings indicate that LCs may contribute to T cell tolerance in the epidermis.

Hydrochlorothiazide disrupts DNA damage response to exacerbate skin photosensitivity

Hydrochlorothiazide (HCTZ) is a widely utilized diuretic for the treatment of hypertension. The photosensitivity of HCTZ has been recognized for six decades, with UVA being considered the primary culprit. However, the precise molecular mechanism of HCTZ sensitizing skin to UV radiation remains unknown. In this study, we demonstrate that HCTZ exacerbates UVB-induced photosensitivity in normal skin by disrupting the DNA damage response, a crucial network responsible for maintaining epidermal homeostasis. Here, we found that HCTZ aggravates UVB-induced mouse skin damage. Through transcriptomic and proteomic profiling, we have found that the cell cycle and p53 signaling pathway may contribute to the photosensitivity caused by HCTZ. In keratinocytes, HCTZ promotes the transition from G1 to S phase and inhibits the p53 signaling pathway after exposure to UV radiation. We have found that HCTZ enhances the accumulation of DNA damage induced by UVB and impairs nucleotide excision repair (NER), which is responsible for repairing UVB-induced DNA lesions, by inhibiting the expression of NER-related genes and shortening the duration of G1 phase. Furthermore, pharmacologically inducing G1 arrest eliminates HCTZ-induced accumulation of damaged DNA. These findings unveil an unknown mechanism through which HCTZ impairs NER and interferes with UVB-induced cell cycle arrest, ultimately leading to improper response towards DNA damage and increased skin sensitivity.

HOXC10 promotes hypertrophic scar fibroblast fibrosis through the regulation of STMN2 and the TGF-β/Smad signaling pathway.

The pathophysiology of hypertrophic scar (HS) shares similarities with cancer. HOXC10, a gene significantly involved in cancer development, exhibits higher expression levels in HS than in normal skin (NS), suggesting its potential role in HS regulation. And the precise functions and mechanisms by which HOXC10 influences HS require further clarification. Gene and protein expressions were analyzed using raeal-time quantitative polymerase chain reaction (RT-qPCR) and western blot techniques. Cell proliferation and migration were evaluated using EdU proliferation assays, CCK-8 assays, scratch assays, and Transwell assays. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were conducted to investigate the interactions between HOXC10 and STMN2. HOXC10 and STMN2 expression levels were significantly higher in HS tissues compared with NS tissues. Silencing HOXC10 led to decreased activation, proliferation, migration, and fibrosis in hypertrophic scar fibroblasts (HSFs). Our findings also indicate that HOXC10 directly targets STMN2. The promotional effects of HOXC10 knockdown on HSF activation, proliferation, migration, and fibrosis were reversed by STMN2 overexpression. We further demonstrated that HOXC10 regulates HSF activity through the TGF-β/Smad signaling pathway. HOXC10 induces the activation and fibrosis of HSFs by promoting the transcriptional activation of STMN2 and engaging the TGF-β/Smad signaling pathway. This study suggests that HOXC10 could be a promising target for developing treatments for HS.

NEDD4L Inhibits the Proliferation and Migration of Keloid Fibroblasts by Regulating YY1 Ubiquitination-Mediated Glycolytic Metabolic Reprogramming.

Keloid scarring is a complex fibroproliferative disorder characterised by excessive fibroblast proliferation. Inhibition of cellular glycolysis effectively suppresses the proliferation of keloid fibroblasts (KFs). Neural precursor cell-expressed developmentally downregulated gene 4-like (NEDD4L), a ubiquitin ligase, regulates cell proliferation in different diseases. This study investigated the effects of NEDD4L on glucose metabolism, proliferation and migration in KFs. Primary KFs were isolated from keloid skin tissues obtained from patients with active-stage keloids. Cell transfection was used to upregulate or downregulate NEDD4L and Yin Yang 1 (YY1) in KFs. Protein expression was assessed by immunohistochemistry and western blotting. The viability, proliferative capacity and migration ability of KFs were evaluated using the MTT method and the EdU and wound healing assays, respectively. The regulatory effect of NEDD4L on YY1 ubiquitination was examined by coimmunoprecipitation. The interaction between YY1 and hexokinase 2 (HK2) was confirmed by a dual-luciferase reporter assay. NEDD4L was downregulated, whereas YY1 and HK2 were highly expressed in keloid tissues compared with normal skin. Overexpression of NEDD4L inhibited the proliferation and migration of KFs. NEDD4L promoted YY1 degradation in KFs by inducing its ubiquitination. Upregulation of YY1 induced glucose consumption and lactate production in KFs via the transcriptional regulation of HK2. Increased expression of YY1 reversed the reduced viability, proliferation, and migration of KFs overexpressing NEDD4L. YY1 also reversed the NEDD4L-induced inhibition of glucose consumption and lactate production in KFs. Additionally, an invivo study confirmed the inhibitory roles of NEDD4L overexpression and YY1 knockdown in keloid formation. NEDD4L suppressed the viability, proliferation and migration of KFs by regulating YY1 ubiquitination-mediated glycolysis through HK2. These findings suggest a novel regulatory axis, NEDD4L/YY1/HK2, that mediates glucose metabolism in keloid formation.

Disabled 2 (Dab2) Regulates Tumour Progression in Skin Squamous Cell Carcinoma.

Dab2 is an endocytic adaptor protein involved in various physiological processes and signaling pathways. Dab2 is deregulated in various cancers; however, its role in skin squamous cell carcinoma ( SCC) has not been elucidated yet. In the present study, we used the DMBA/TPA induced murine skin carcinogenesis model to examine the role of Dab2 in skin tumour progression. We generated tamoxifen inducible Dab2 conditional knockout system for our study. Loss of Dab2 led to delayed papilloma initiation and reduced papilloma burden. Delayed papilloma initiation was due to reduce proliferative potential of the papillomas due to Dab2 loss. Furthermore, while the WT papillomas progressed to SCC, the papillomas formed in Dab2 cKO mice failed to undergo malignant conversion to SCC. Dab2 cKO tumours showed reduced expression of K8, a marker for aggressive tumour. Moreover, Dab2 ckO tumours failed to undergo EMT as shown by reduced expression of Vimentin and Twist1. Dab2 cKO tumours also showed reduced expression of Sox2, a stem cell marker. Furthermore, qPCR analysis showed upregulation of Dab2 expression in the human skin cancer cell lines as compared to normal human skin keratinocytes. In patients, TCGA data analysis of skin cancer melanoma (SKCM) showed a trend where high levels of Dab2 correlated with poor overall survival. The present study shows that Dab2 promotes tumour progression in skin SCC.

Integrating multiomics sequencing analyses uncover the key mechanisms related to oxidative stress, mitochondria, and immune cells in keloid

BackgroundThis study aimed to investigate the key molecular mechanisms underlying keloid pathogenesis by integrating oxidative stress, mitochondria, and immune cells. MethodsTranscriptome sequencing (mRNA, lncRNA, and circRNA expression data), proteomic sequencing, and small RNA sequencing analyses of lesional and non-lesional skin of patients with keloids and healthy control (normal) skin were conducted. By integrating mRNA and publicly available gene expression data (GSE158395), differentially expressed genes related to oxidative stress and mitochondrial function in keloids were identified. Hub genes were identified using various bioinformatics analyses such as immune infiltration analysis, weighted gene co-expression network analysis, machine learning, and expression validation using proteomics sequencing data. Moreover, a competing endogenous RNA (ceRNA) network of hub genes was constructed by combining miRNA, lncRNA, and circRNA expression data. Five hub genes were identified: MGST1, DHCR24, ALDH3A2, ADH1B, and FKBP5. ResultsThese hub genes had a high diagnostic value for keloids, with an AUC value > 0.8 each. In addition, five hub genes were associated with the infiltration of multiple immune cells. The immune cells with the strongest positive and negative correlations with hub genes were M0 and M1 macrophages. A ceRNA network was constructed, and several ceRNAs, such as AC005062.1/miR-134-5p/FKBP5 and BASP1-AS1/miR-503-5p/ADH1B, were identified. These five hub genes may contribute to keloid pathogenesis. ConclusionThese genes and their related ceRNAs may serve as diagnostic biomarkers and therapeutic targets for keloids.

Translation Prospects of a Novel ECM‐Silk Fibroin/Alginate 3D‐Printed Scaffold for Treatment of Full‐Thickness Skin Wounds: An In Vitro and In Vivo Study

ABSTRACTThe development of bioinks incorporating extracellular matrix (ECM) has attracted significant interest for creating three‐dimensional (3D)‐printed structures that simulate natural skin, aiming to facilitate profound wound healing. In our study, we utilized the potential of human placenta, renowned for its abundant structural proteins and growth factors essential for wound recovery, as a basis for an ECM‐based bioink. Different concentrations (1.5%, 3% and 5% w/v) of decellularized/solubilized placental ECM were integrated into silk fibroin/alginate to generate a printable bioink. The biocompatibility of the printed hydrogels was studied in vitro. Our refined ECM‐based bioink at a 5% w/v concentration was administered to full‐thickness wounds in a mouse model. The ECM‐based frameworks, due to their distinct structure, created a non‐cytotoxic environment conducive to in vitro cell adhesion, infiltration, and proliferation. Crucially, they did not provoke an adverse immune reaction in the host. Implanting the 3D‐printed ECM scaffold into deep wounds resulted in increased formation of granulation tissue, angiogenesis, and re‐epithelialization compared to scaffolds lacking ECM and untreated wounds. Our findings decisively demonstrate that the 5% ECM 3D scaffold promotes regeneration of deep wounds in vivo, creating a skin substitute with cellular organization closely resembling normal skin. This advancement sets the stage for future clinical exploration and holds tremendous promise for advancing wound healing therapies.

Profiling of Toll-like Receptors and Related Signaling Mediators in the Pathogenesis of Morphea

Introduction: Morphea, also known as localized scleroderma, is a rare fibrosing inflammatory disease of unknown pathogenesis. Objectives: Although the genetic basis for morphea is important, the evaluation of Toll-like receptors (TLR) in this disease is quite limited. We aimed to evaluate TLR expression levels and serum IL-6, IL-17A, TGF-b1, FGF, and VEGF levels in patients with morphea, and compare these results with healthy controls. Methods: The expression levels of TLRs in the lesional and non-lesional adjacent skin of patients with morphea, and normal skin of healthy controls were evaluated by RT-PCR whereas serum levels of IL-6, IL-17A, TGF-b1, FGF, and VEGF were evaluated by ELISA. Results: Based on our findings, TLR1 gene expression increased 34.3-fold in the lesional skin of patients with morphea. In addition, IL-6, IL-17A, TGF-β, FGF and VEGF were found to be higher in the blood samples of the patient group than in the healthy group. Conclusion: TLRs are important parts of the pathogenesis of morphea, and a better understanding of it will lead to more directed and effective treatments. We believe that this study will be important for pioneering TLR-targeted therapeutic approaches in the treatment of morphea in the future.

Antiproliferative and biochemical evaluation of rose extracts: impact on tumor and normal skin cells.

Rose petals (Rosa L.) are rich sources of phenolic compounds, including anthocyanins. Anthocyanins and anthocyanidins are associated with multiple health benefits due to their antioxidant properties. In this study, eighteen rose cultivars were comparatively analyzed to determine their total polyphenol and flavonoid content, as well as their antioxidant activity using the 2,2-diphenylpicrylhydrazyl (DPPH) radical scavenging method. The extracts were purified using Amberlite XAD-7 and Sephadex LH-20 columns to obtain anthocyanin-rich fractions. Individual anthocyanins were separated and identified using high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS). The three cultivars with the highest anthocyanin content were further examined for cytotoxic effects on cell cultures at various extract concentrations (200-1000 µg/mL) using two skin cell lines: a melanoma cell line (A375) and a normal skin cell line (Hs27). The HPLC-MS analysis identified nine different anthocyanin compounds, with the total anthocyanin content in the rose cultivars varying from 12.42 to 331.95 mg of cyanidin-3-glucoside equivalent/100g of fresh weight. The total polyphenol and total flavonoid contents ranged from 289 to 2703 mg gallic acid equivalent/100g fresh weight and 102 to 603 mg catechin equivalent/100g fresh weight, respectively. Antioxidant activity ranged from 450 to 1304 µmol trolox equivalent/g fresh weight. A significant correlation was observed between antioxidant activity and the content of anthocyanins (R = 0.875, p < 0.001), flavonoids (R = 0.982, p < 0.001), and polyphenols (R = 0.991, p < 0.001). Furthermore, principal component analysis, along with dendrograms and heatmaps, illustrated the relationships among these key compounds and their association with antioxidant activity. The MTT assay showed a substantial suppression of A375 cancer skin cells, while simultaneously exhibiting cell proliferation in Hs27 normal skin cells in a concentration-dependent manner. Altogether, results suggest that the anthocyanins from these rose cultivars could be considered as a promising agent for adjuvant treatment of skin melanoma.

Exploring the Safety of the Sustainable Toxicity Testing in Zebrafish and Brine Shrimp Using Nanoemulsions Formulated from Fish Byproducts and Lemon Oil

Nanoemulsions, characterized by their nanosized particles ranging from 20 to 200 nm, are effective carriers for drug molecules. Our novel oil-in-water nanoemulsion, NE-FLO™, formulated from lemon and fish byproduct oils, demonstrates promising antioxidant and anti-inflammatory activities, with initial studies indicating nontoxicity to normal skin cells. This study investigated the safety of NE-FLO™ using brine shrimp (Artemia salina) and zebrafish (Danio rerio) models, focusing on concentration-dependent effects and LC50 values. At lower concentrations (0.1 mg·L−1, 0.01 mg·L−1, and 0.001 mg·L−1), NE-FLO™ showed minimal toxicity without adverse effects. However, at 1 mg·L−1, reduced survival rates indicate potential toxicity. Specifically, this concentration also induces altered swimming behaviors in zebrafish. LC50 values are 8.7474 mg·L−1 for brine shrimp and 0.316 mg·L−1 for adult zebrafish. These results underscore the necessity for further detailed investigations into NE-FLO™, balancing its therapeutic benefits with potential toxicity risks. This study emphasizes the importance of optimizing nanoemulsion formulations from fish oil and conducting comprehensive safety assessments to meet regulatory standards.

DMA‐Net: A dual branch encoder and multi‐scale cross attention fusion network for skin lesion segmentation

AbstractAutomatic segmentation of skin lesion is an important step in computer‐aided diagnosis. However, due to the significant variations in the size and shape of the lesion areas, as well as the low contrast with normal skin tissue, the boundaries are not clearly distinguishable, leading to a high possibility of incorrect segmentation. Therefore, this task is highly challenging. To overcome these difficulties, this paper proposes a medical image segmentation architecture named dual branch encoder and multi‐scale cross attention fusion network, which includes a dual‐branch encoder based on convolutional neural network and an improved channel‐enhanced Mamba to comprehensively extract local and global information from dermoscopy images. Additionally, to enhance the feature interaction and fusion of local and global information, a multi‐scale cross attention fusion module is adopted to cross‐merge features in different directions and at different scales, maximizing the advantages of the dual‐branch encoder and achieving precise segmentation of skin lesions. Extensive experiments are conducted on three public skin lesion datasets: ISIC‐2018, ISIC‐2017, and ISIC‐2016, to verify the effectiveness and superiority of the proposed method. The dice similarity coefficient scores on the three datasets reached 81.77%, 81.68% and 85.60%, respectively, surpassing most state‐of‐the‐art methods.

Immunohistochemical Expression of Immune Regulatory Proteins in Interface Dermatoses.

Cutaneous immune-related adverse events (irAEs) of immunotherapies, such as anti-programmed cell death protein-1 (PD-1), suggest that immune checkpoint factors may contribute to the pathobiology of lichenoid interface dermatitis in immunotherapy-naïve patients. Our study aimed to describe innate and adaptive immune markers via immunohistochemical (IHC) staining of lichenoid interface dermatoses. We studied the staining patterns of PD-L1, STING, IL-36 gamma, CD8, PD-1, and LAG-3 in five interface dermatoses: oral lichen planus (LP) (n = 10), cutaneous LP (n = 10), chronic cutaneous lupus erythematosus (CLE) (n = 11), erythema multiforme (EM) (n = 11), and toxic epidermal necrolysis (TEN) (n = 13), by immunohistochemistry (IHC) analysis. Expression was evaluated semi-quantitively according to the percentage of keratinocytes and dermal lymphocytes stained compared to keratinocytes and resident pericapillary lymphocytes in normal human skin. All interface dermatoses evaluated showed increased expression of PD-L1 on keratinocytes and LAG-3 in lymphocytes. STING was increased on the keratinocytes of most specimens. Expression of IL-36 gamma, in basal layer keratinocytes was more extensive in oral LP and cutaneous LP and varied in CLE, EM, and TEN. Lymphocytic infiltration expressing PD-1 was elevated in oral LP, cutaneous LP, and CLE. Current thinking is that interface dermatitis is the result of a cell-mediated immune reaction involving cytotoxic CD8+ T-cell-mediated apoptosis of keratinocytes. The findings of this study suggest that in addition to cell-mediated immunity, innate immune factors may contribute to pathobiology.

Single-cell RNA sequencing highlights the role of proinflammatory fibroblasts, vascular endothelial cells, and immune cells in the keloid immune microenvironment.

Keloids, characterized by an aberrant wound-healing process and a highly complex immune microenvironment, pose significant challenges for clinical management. Fibroblasts and vascular endothelial cells (VEC) were identified as the leading cells of keloid development. However, their roles in the keloid immune landscape have yet to be thoroughly elucidated. To explore the functional state of cells in the immune landscape of keloids, we conducted a single-cell RNA sequencing analysis on the tissue from three keloid lesions and two specimens of healthy skin. We simultaneously utilized available keloid data from the public database for external validation. Specific subsets, such as proinflammatory fibroblasts (piF) and VEC, were markedly elevated in lesional skincompared to normal skin. Subsequent differential gene expression and Gene Ontology analyses indicated that these subsets may be involved in shaping the microenvironment. In keloids, there is an increased expression of immune-associated genes (P < 0.05), including TNFRSF6B, HGF, and TGFB3, alongside a decreased expression of inflammatory chemokines in the piF. Moreover, the significant upregulation of immune suppressive genes (P < 0.05), including CD39, CD73, and HIF1A, suggested the potential involvement of VEC as a conditional immune subpopulation in the keloid microenvironment. Immune cell communication analysis revealed preferential enrichment of macrophages and Tregs, highlighting intensified macrophage-centered interactions within the keloid microenvironment. Our study highlighted the role of piF and VEC in the immune microenvironment of keloids for the first time, providing potential targets for therapeutic development.

Expression of TRPS1 in Metastatic Tumors of the Skin: An Immunohistochemical Study of 72 Cases

TRPS1 (Tricho-rhino-phalangeal syndrome 1) is a GATA transcriptional activator gene encoding for a protein used as a sensitive immunohistochemical marker of breast carcinomas. In dermatopathology, TRPS1 is used as a marker of mammary and extramammary Paget’s disease and is also expressed by a variety of primary cutaneous tumors, mostly of adnexal origin. So far, very limited data exist on the expression of TRPS1 in metastatic skin tumors. We studied the immunohistochemical expression of TRPS1 in 72 cutaneous metastatic tumors from the breast (n: 19) and other origins (n: 53) in order to assess its diagnostic usefulness. The intensity of TRPS1 immunostaining was expressed as a histoscore: the product of the percentage of positive cells (scored semi-quantitatively 0–4) and the staining intensity (scored 0–3). In normal skin, nuclear TRPS1 expression was predominantly observed in cells of adnexal structures (pilosebaceous follicles and sweat glands). Eighteen (18/19, 94.7%) metastatic breast carcinomas showed diffuse and strong TRPS1 positivity (histoscore 12). Lower reactivity was found in some other metastases, including from the lung (11/22), the female genital tract (3/4), and the kidney (2/4), whereas most (20/22) metastases from the digestive system and peritoneum, along with a case of metastatic prostate carcinoma, were negative. These results suggest that a high histoscore for TRPS1 is in favor of the mammary origin of metastatic cutaneous carcinoma. Although TRPS1 is not absolutely specific or sensitive to a particular primary, we consider that it can be added to a panel of other markers when investigating the origin of a cutaneous metastasis, namely when this is the first manifestation of the neoplastic disease.