Atopic Dermatitis Lesions Research Articles

Histamine and Th2 cytokines independently and synergistically upregulate MMP12 expression in human M2 macrophages

Beyond Th2 cells and various immune cells, M2 macrophages have been identified in lesional skin of atopic dermatitis (AD) indicating their involvement in the disease’s underlying mechanisms. MMP12, a matrix-degrading enzyme, which is predominantly produced by macrophages, is increased in skin lesions of AD patients. In this study we investigated the expression of MMP12 mRNA in lesional AD skin at single cell level through RNA sequencing (scRNA-seq) and the expression of MMP12 in M2 macrophages from healthy individuals and AD patients in response to Th2 cytokines and histamine using quantitative PCR and ELISA. Additionally, we analyzed macrophages from dupilumab-treated AD patients using the same methods to assess the influence of Th2 cytokines on MMP12 expression ex-vivo. ScRNA-seq identified macrophages as the primary producers of MMP12 in lesional AD skin. In-vitro, both MMP12 mRNA and protein expression were significantly increased in monocytes during differentiation to M2 macrophages in the presence of histamine, of Th2 cytokines or of Th2 cytokines in combination with histamine. In M2 macrophages obtained from dupilumab-treated AD patients, the upregulation of MMP12 expression by IL-4 and IL-13 was attenuated. Our findings unveil a novel mechanism whereby Th2 cytokines and histamine regulate MMP12 expression, potentially impacting skin barrier homeostasis in AD.

The levels of amino acid metabolites in serum induce the pathogenesis of atopic dermatitis by mediating the inflammatory protein S100A12

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.

Oral Administration of Taurodeoxycholate, A GPCR19 Agonist, Effectively Ameliorates Atopic Dermatitis in A Mouse Model.

Atopic dermatitis (AD) is the most prevalent chronic inflammatory skin disorder, characterised by intense pruritus and recurrent eczematous lesions. Recently, the US FDA has approved Janus kinase (JAK) inhibitors for oral treatment in AD patients. However, oral immunomodulatory agents have demonstrated adverse effects. In previous studies, we demonstrated the efficacy of topical taurodeoxycholate (TDCA), a G protein-coupled receptor 19 (GPCR19) agonist, on AD. In this study, we further evaluated the efficacy of orally administered TDCA on MC903- and dinitrochlorobenzene (DNCB)-induced AD mouse models. Oral administration of TDCA significantly ameliorated AD symptoms and reduced both epidermal and dermal thickness. Additionally, oral TDCA treatment inhibited the infiltration of myeloid and lymphoid cells into AD lesions. TDCA also suppressed the expression of thymic stromal lymphopoietin (TSLP), interleukin (IL)-4, IL-13, IL-33, IL-1β, tumour necrosis factor-alpha (TNF-α) and chemokine (C-C motif) ligand 17 in the skin and blood. Given the previously demonstrated safety profiles of TDCA, oral TDCA may offer a beneficial and safer alternative for AD patients.

Co-Expression Network and Machine Learning Analysis of Transcriptomics Data Identifies Distinct Gene Signatures and Pathways in Lesional and Non-Lesional Atopic Dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin condition with complex origins. Current treatments often yield suboptimal results due to an incomplete understanding of its underlying mechanisms. This study aimed to identify pathway and gene signatures that distinguish between lesional AD, non-lesional AD, and healthy skin. We conducted differential gene expression and co-expression network analyses to identify differentially co-expressed genes (DCEGs) in lesional AD vs. healthy skin, lesional vs. non-lesional AD, and non-lesional AD vs. healthy skin. Modules associated with lesional and non-lesional AD were identified based on the correlation coefficients between module eigengenes and clinical phenotypes (|R| ≥ 0.5, p-value < 0.05). Subsequently, we employed Ingenuity Pathway Analysis (IPA) on the identified DCEGs, followed by machine learning (ML) analysis within the pathway expression framework. The ML analysis of pathway expressions, selected by IPA and derived from gene expression data, identified relevant pathway signatures, which were validated using an independent dataset and correlated with AD severity measures (EASI and SCORAD). We identified 975, 441, and 40 DCEGs in lesional vs. healthy skin, lesional vs. non-lesional, and non-lesional vs. healthy skin, respectively. IPA and ML analyses revealed 25 relevant pathway signatures, including wound healing, glucocorticoid receptor signaling, and S100 gene family signaling pathways. Validation confirmed the significance of 10 pathway signatures, which were correlated with the AD severity measures. DCEGs such as MMP12 and S100A8 demonstrated high diagnostic efficacy (AUC > 0.70) in both the discovery and validation datasets. Differential gene expression, co-expression networks and ML analyses of pathway expression have unveiled relevant pathways and gene signatures that distinguish between lesional, non-lesional, and healthy skin, providing valuable insights into AD pathogenesis.

Epidermal renewal during the treatment of atopic dermatitis lesions: A study coupling line‐field confocal optical coherence tomography with artificial intelligence quantifications

AbstractObjectiveThis study explores the application of Line‐field Confocal Optical Coherence Tomography (LC‐OCT) imaging coupled with artificial intelligence (AI)‐based algorithms to investigate atopic dermatitis (AD), a common inflammatory dermatosis.Materials and methodsAD acute and chronic lesions (ADL) were compared to clinically healthy‐looking skin (ADNL). LC‐OCT was used noninvasively and in real‐time to image the skin of AD patients during flare‐ups and monitor remissions under topical steroid treatment for 2 weeks. Quantitative parameters were extracted from the images, including morphological and cellular‐level markers of epidermal architecture. A novel cellular‐level parameter, nuclei “atypia,” which quantifies the orderliness of epidermal renewal, was used to highlight abnormal maturation processes.ResultsCompared to healthy skin, AD lesions exhibited significant increases in both epidermal and stratum corneum (SC) thickness, along with a more undulated dermo‐epidermal junction (DEJ). Additionally, keratinocyte nuclei (KN) were larger, less compact, and less organized in lesional areas, as indicated by the atypia parameter. A higher degree of atypia was observed in chronic lesions compared to acute ones. Following treatment, all the parameters normalized to levels observed in healthy skin within 2 weeks, mirroring clinical improvements.ConclusionThis study provides insights into the quantification of epidermal renewal using a noninvasive imaging technique, highlighting differences between ADL/ADNL and acute/chronic lesions. It also presents the AD treatment mechanism, paving the way for future investigations on AD and other skin barrier function‐related conditions.

Heterogeneous IL-9 Production by Circulating Skin-Tropic and Extracutaneous Memory T Cells in Atopic Dermatitis Patients.

Interleukin (IL)-9 is present in atopic dermatitis (AD) lesions and is considered to be mainly produced by skin-homing T cells expressing the cutaneous lymphocyte-associated antigen (CLA). However, its induction by AD-associated triggers remains unexplored. Circulating skin-tropic CLA+ and extracutaneous/systemic CLA- memory T cells cocultured with autologous lesional epidermal cells from AD patients were activated with house dust mite (HDM) and staphylococcal enterotoxin B (SEB). Levels of AD-related mediators in response to both stimuli were measured in supernatants, and the cytokine response was associated with different clinical characteristics. Both HDM and SEB triggered heterogeneous IL-9 production by CLA+ and CLA- T cells in a clinically homogenous group of AD patients, which enabled patient stratification into IL-9 producers and non-producers, with the former group exhibiting heightened HDM-specific and total IgE levels. Upon allergen exposure, IL-9 production depended on the contribution of epidermal cells and class II-mediated presentation; it was the greatest cytokine produced and correlated with HDM-specific IgE levels, whereas SEB mildly induced its release. This study demonstrates that both skin-tropic and extracutaneous memory T cells produce IL-9 and suggests that the degree of allergen sensitization reflects the varied IL-9 responses in vitro, which may allow for patient stratification in a clinically homogenous population.

Genomic analysis and identification of a novel superantigen, SargEY, in Staphylococcus argenteus isolated from atopic dermatitis lesions.

Staphylococcus aureus is frequently isolated from active lesions of atopic dermatitis (AD) patients. We reported that 17%-22% of S. aureus isolated from AD patients produced a novel superantigen staphylococcal enterotoxin Y (SEY). Unlike many S. aureus superantigens that activate T cells via T-cell receptor (TCR) Vß, SEY activates T cells via TCR Vα and stimulates cytokine secretion. Staphylococcus argenteus was isolated from AD patients during the surveillance for S. aureus. Phylogenetic comparison of the genome indicated that the isolate was very similar to S. aureus causing skin infections. The isolate encoded a SEY-like protein, designated SargEY, which, like SEY, activated T cells via the TCR Vα. ST2250 is the only lineage positive for SargEY gene. ST2250 S. argenteus harboring a superantigen SargEY gene may be a novel staphylococcal clone that infects human skin and is involved in the exacerbation of AD.

Glucocorticoid receptor controls atopic dermatitis inflammation via functional interactions with P63 and autocrine signaling in epidermal keratinocytes

Atopic dermatitis (AD), a prevalent chronic inflammatory disease with multifactorial etiology, features epidermal barrier defects and immune overactivation. Synthetic glucocorticoids (GCs) are widely prescribed for treating AD due to their anti-inflammatory actions; however, mechanisms are incompletely understood. Defective local GC signaling due to decreased production of endogenous ligand and/or GC receptor (GR) levels was reported in prevalent inflammatory skin disorders; whether this is a consequence or contributing factor to AD pathology is unclear. To identify the chromatin-bound cell-type-specific GR protein interactome in keratinocytes, we used rapid immunoprecipitation of endogenous proteins and mass spectrometry identifying 145 interactors that increased upon dexamethasone treatment. GR-interacting proteins were enriched in p53/p63 signaling, including epidermal transcription factors with critical roles in AD pathology. Previous analyses indicating mirrored AD-like phenotypes between P63 overexpression and GR loss in epidermis, and our data show an intricate relationship between these transcription factors in human keratinocytes, identifying TP63 as a direct GR target. Dexamethasone treatment counteracted transcriptional up-regulation of inflammatory markers by IL4/IL13, known to mimic AD, causing opposite shifts in GR and P63 genomic binding. Indeed, IL4/IL13 decreased GR and increased P63 levels in cultured keratinocytes and human epidermal equivalents (HEE), consistent with GR down-regulation and increased P63 expression in AD lesions vs normal skin. Moreover, GR knockdown (GRKD) resulted in constitutive increases in P63, phospho-P38 and S100A9, IL6, and IL33. Also, GRKD culture supernatants showed increased autocrine production of TH2-/TH1-/TH17-TH22-associated factors including IL4, CXCL10, CXCL11, and CXCL8. GRKD HEEs showed AD-like features including hyperplasia and abnormal differentiation, resembling phenotypes observed with GR antagonist or IL4/IL13 treatment. The simultaneous GR/P63 knockdown partially reversed constitutive up-regulation of inflammatory genes in GRKD. In summary, our data support a causative role for GR loss in AD pathogenesis via functional interactions with P63 and autocrine signaling in epidermal keratinocytes.

Distinct maturation, glucose metabolism, and inflammatory function of human monocytes-derived IDECs mediated by anti-IgE and Pam3CSK4 alone or in combination.

Cell energy metabolism controls the activation and function of dendritic cells (DCs). Inflammatory dendritic epidermal cells (IDECs) in skin lesions of atopic dermatitis (AD) express high-affinity IgE receptor (FcϵRI) and toll-like receptor 2 (TLR2), which mediate the generation and maintenance of inflammation. However, cellular energy metabolism and effector function of IDECs mediated by FcϵRI and TLR2 have not been fully elucidated. IDECs in vitro were treated with TLR2 agonist Pam3CSK4 and anti-IgE alone or in combination for 24h. Further, we analyzed the expression of cell surface activation markers, production of inflammatory factors, and cellular energy metabolism profiles of IDECs by using flow cytometry, multiplex assay, RNA sequencing, targeted energy metabolism, and seahorse assays. Compared to the unstimulated or anti-IgE groups, Pam3CSK4 alone or combined with anti-IgE groups significantly increased the expression of CD80, CD83, and CD86 on IDECs, but did not affect the expression of the above markers in the anti-IgE group. The release of inflammatory cytokines increased in the Pam3CSK4 alone or combined with anti-IgE groups, while there was a weak increasing trend in the anti-IgE group. The glycolysis/gluconeogenesis pathway of carbon metabolism was affected in all treatment groups. Furthermore, compared to the control group, we found a decrease in pyruvic acid, upregulation of PFKM, downregulation of FBP1, and increase in extracellular lactate, glycolysis rate, and glycolysis capacity after all treatments, while there was no difference between each treatment group. However, there was no difference in glycolytic reserve and mitochondrial basic and maximum respiration among all groups. Our results indicate that glycolysis of IDECs may be activated through FcϵRI and TLR2 to upregulate inflammatory factors, suggesting that danger signals from bacteria or allergens might evoke an inflammatory response from AD through the glycolysis pathway.

Characterization of Inflammatory Mediators and Metabolome in Interstitial Fluid Collected with Dermal Open Flow Microperfusion before and at the End of Dupilumab Treatment in Atopic Dermatitis.

Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.

Mapping the Periostin splice isoforms in atopic dermatitis and an in vitro asthma model – A multi-platform analysis using mass spectrometry and RT-qPCR

Periostin is a matricellular protein known to be alternatively spliced to produce ten isoforms with a molecular weight of 78–91 kDa. Within the extracellular matrix, periostin attaches to cell surfaces to induce signaling via integrin-binding and actively participates in fibrillogenesis, orchestrating the arrangement of collagen in the extracellular environment. In atopic diseases such as atopic dermatitis (AD) and asthma, periostin is known to participate in driving the disease-causing type 2 inflammation. The periostin isoforms expressed in these diseases and the implication of the alternative splicing events are unknown. Here, we present two universal assays to map the expression of periostin isoforms at the mRNA (RT-qPCR) and protein (PRM-based mass spectrometry) levels. We use these assays to study the splicing profile of periostin in AD lesions as well as in in vitro models of AD and asthma. In these conditions, periostin displayed overexpression with isoforms 3 and 5 standing out as highly overexpressed. Notably, isoforms 9 and 10 exhibited a divergent pattern relative to the remaining isoforms. Isoforms 9 and 10 are often overlooked in periostin research and this paper presents the first evidence of their expression at the protein level. This underlines the necessity to include isoforms 9 and 10 in future research addressing periostin splice isoforms. The assays presented in this paper hold the potential to improve our insight into the splicing profile of periostin in tissues and diseases of interest. The application of these assays to AD lesions and in vitro models demonstrated their potential for identifying isoforms of particular significance, warranting a further in-depth investigation.

Superantigen Encoding Genes in Staphylococcus aureus Isolated from Lesional Skin, Non-Lesional Skin, and Nares of Patients with Atopic Dermatitis.

Patients with atopic dermatitis (AD) are more likely than healthy individuals to harbour Staphylococcus aureus on their skin. Superantigens (SAgs) produced by specific S. aureus strains may contribute to AD-associated skin inflammation. The present study compared the prevalence and types of SAg-encoding genes between S. aureus isolated from patients with AD and from controls, and within the AD group between isolates from different sampling sites (lesional skin, non-lesional skin, and nares). This retrospective case-control study extracted data from 2 previous studies that examined S. aureus using whole-genome sequencing. The 138 S. aureus isolates obtained from 71 AD patients contained 349 SAg-encoding genes; 22 (6.3%) were found in isolates from nares (0.4 ± 0.6 genes per isolate), 99 (28.4%) in isolates from non-lesional skin (3.7 ± 3.9), and 228 (65.3%) in isolates from lesional skin (4.2 ± 4.5). S. aureus (n = 101) from the control group contained 594 SAg-encoding genes (5.9 ± 4.2). Of the S. aureus isolated from lesional AD skin, 69% carried at least 1 gene encoding SAg compared with 33% of AD nasal isolates. SAg could be a factor in the pathogenesis of a subset of AD patients.

HISTOPATHOLOGICAL FEATURES OF DOGS SKIN WITH ATOPIC DERMATITIS AFTER TREATMENT USING ECO ENZYME

Atopic dermatitis is one of the most common diseases in dogs that is multifactorial and usually attacks dogs aged between 6-36 months. This study was aimed to determine the histopathological appearance of the skin of dogs suffering from atopic dermatitis after treated with eco enzyme. Eco enzyme is a liquid product resulting from the fermentation of organic kitchen waste product such as fruit and vegetable dregs, molasses, and water. This study used five dogs suffering from atopic dermatitis which were divided into two groups. Group A: three dogs samples were bathed with 10% eco enzyme liquid every three days for 28 days. In Group B: two samples of dogs were bathed with 10% eco enzyme every three days until the 9th day, followed by a 2% eco enzyme bath once a week (13th, 20th, 27th day). Both treatment groups started from day 0 until day 28. Skin samples were taken using the biopsy method and histopathological changes were observed by making histopathological skin preparations stained with Hematoxylin and Eosin. Observations of the preparations were carried out using a light microscope. Data were analyzed using the Analysis of Variance test followed by the Duncan multiple range test and the Kruskall Wallis test followed by the Mann-Whitney test, then the data was explained descriptively. The results of the Anova test showed that the thickness of the dogs epidermis treated with 2% and 10% eco enzyme was significantly different (P&lt;0.05). The Kruskall Wallis test for scoring inflammatory cell infiltration and degeneration showed that there was a significant difference (P&lt;0.05) in the administration of 2% and 10% eco enzyme. Eco enzyme liquid is able to reduce atopic dermatitis lesions in dogs. Giving eco enzyme at a concentration of 10% and followed by a concentration of 2% with an extended application time can return the histological structure of the dog’s skin to normal, especially the thickness of the epidermis, reduce inflammatory cell infiltration, and reduce degeneration.

MicroRNA-939 amplifies Staphylococcus aureus-induced matrix metalloproteinase expression in atopic dermatitis.

Atopic dermatitis (AD) is a common chronic inflammatory skin diseases that seriously affects life quality of the patients. Staphylococcus aureus (S. aureus) colonization on the skin plays an important role in the pathogenesis of AD; however, the mechanism of how it modulates skin immunity to exacerbate AD remains unclear. MicroRNAs are short non-coding RNAs that act as post-transcriptional regulators of genes. They are involved in the pathogenesis of various inflammatory skin diseases. In this study, we established miRNA expression profiles for keratinocytes stimulated with heat-killed S. aureus (HKSA). The expression of miR-939 in atopic dermatitis patients was analyzed by fluorescence in situ hybridization (FISH). miR-939 mimic was transfected to human primary keratinocyte to investigate its impact on the expression of matrix metalloproteinase genes (MMPs) in vitro. Subsequently, miR-939, along with Polyplus transfection reagent, was administered to MC903-induced atopic dermatitis skin to assess its function in vivo. MiR-939 was highly upregulated in HKSA-stimulated keratinocytes and AD lesions. In vitro studies revealed that miR-939 increased the expression of matrix metalloproteinase genes, including MMP1, MMP3, and MMP9, as well as the cell adhesion molecule ICAM1 in human primary keratinocytes. In vivo studies indicated that miR-939 increased the expression of matrix metalloproteinases to promote the colonization of S. aureus and exacerbated S. aureus-induced AD-like skin inflammation. Our work reveals miR-939 is an important regulator of skin inflammation in AD that could be used as a potential therapeutic target for AD.

Discovery of biomarkers in the psoriasis through machine learning and dynamic immune infiltration in three types of skin lesions.

Psoriasis is a chronic skin disease characterized by unique scaling plaques. However, during the acute phase, psoriatic lesions exhibit eczematous changes, making them difficult to distinguish from atopic dermatitis, which poses challenges for the selection of biological agents. This study aimed to identify potential diagnostic genes in psoriatic lesions and investigate their clinical significance. GSE182740 datasets from the GEO database were analyzed for differential analysis; machine learning algorithms (SVM-RFE and LASSO regression models) are used to screen for diagnostic markers; CIBERSORTx is used to determine the dynamic changes of 22 different immune cell components in normal skin lesions, psoriatic non-lesional skin, and psoriatic lesional skin, as well as the expression of the diagnostic genes in 10 major immune cells, and real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry are used to validate results. We obtained 580 differentially expressed genes (DEGs) in the skin lesion and non-lesion of psoriasis patients, 813 DEGs in mixed patients between non-lesions and lesions, and 96 DEGs in the skin lesion and non-lesion of atopic dermatitis, respectively. Then 144 specific DEGs in psoriasis via a Veen diagram were identified. Ultimately, UGGT1, CCNE1, MMP9 and ARHGEF28 are identified for potential diagnostic genes from these 144 specific DEGs. The value of the selected diagnostic genes was verified by receiver operating characteristic (ROC) curves with expanded samples. The the area under the ROC curve (AUC) exceeded 0.7 for the four diagnosis genes. RT-qPCR results showed that compared to normal human epidermis, the expression of UGGT1, CCNE1, and MMP9 was significantly increased in patients with psoriasis, while ARHGEF28 expression was significantly decreased. Notably, the results of CIBERSORTx showed that CCNE1 was highly expressed in CD4+ T cells and neutrophils, ARHGEF28 was also expressed in mast cells. Additionally, CCNE1 was strongly correlated with IL-17/CXCL8/9/10 and CCL20. Immunohistochemical results showed increased nuclear expression of CCNE1 in psoriatic epidermal cells relative to normal. Based on the performance of the four genes in ROC curves and their expression in immune cells from patients with psoriasis, we suggest that CCNE1 possess higher diagnostic value.

Investigating Distinct Skin Microbial Communities and Skin Metabolome Profiles in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by genetic predisposition, environmental factors, immune dysregulation, and skin barrier dysfunction. The skin microbiome and metabolome play crucial roles in modulating the skin's immune environment and integrity. However, their specific contributions to AD remain unclear. We aimed to investigate the distinct skin microbial communities and skin metabolic compounds in AD patients compared to healthy controls (HCs). Seven patients with AD patients and seven HCs were enrolled, from whom skin samples were obtained for examination. The study involved 16S rRNA metagenomic sequencing and bioinformatics analysis as well as the use of gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) to detect metabolites associated with AD in the skin. We observed significant differences in microbial diversity between lesional and non-lesional skin of AD patients and HCs. Staphylococcus overgrowth was prominent in AD lesions, while Cutibacterium levels were decreased. Metabolomic analysis revealed elevated levels of several metabolites, including hypoxanthine and glycerol-3-phosphate in AD lesions, indicating perturbations in purine metabolism and energy production pathways. Moreover, we found a positive correlation between hypoxanthine and glycerol-3-phosphate and clinical severity of AD and Staphylococcus overgrowth. These findings suggest potential biomarkers for monitoring AD severity. Further research is needed to elucidate the causal relationships between microbial dysbiosis, metabolic alterations, and AD progression, paving the way for targeted therapeutic interventions.

Impact of atopic dermatitis lesion locations and extent on patient burden: A real‐world study

AbstractBackgroundAtopic dermatitis (AD) is associated with patient burden, but few studies describe the anatomic distribution of the disease or the impact of number of lesion locations.ObjectivesTo describe lesion locations and assess the relationship between the number of lesion locations (disease extent) and disease burden in patients with AD.MethodsThis cross‐sectional study included adults with dermatologist‐ or dermatology practitioner‐diagnosed AD enroled in the CorEvitas AD Registry (2020–2021) who initiated systemic therapy within 12 months prior to or at enrolment or had moderate‐to‐severe AD (vIGA‐AD® ≥3 and EASI ≥12) at enrolment. Thirteen areas of lesion involvement were assessed using a body map, and numbers of lesion locations were categorised as: 0, 1, 2–3, 4–6 and ≥7. Demographics, disease characteristics, PROs by number of lesion locations were descriptively compared using effect sizes (ES). The ES thresholds for small, medium, and large differences, respectively, were 0.10, 0.30, and 0.50 for phi (categorical outcomes) and 0.10, 0.25 and 0.40 for Cohen's f (continuous outcomes).ResultsAmong 1211 patients, lesion involvement was most frequent on the arms (69.5%) and lower limbs (61.7%). A total of 10.6%, 9.3%, 20.1%, 26.3% and 33.8% of patients had 0, 1, 2–3, 4–6 and ≥7 lesion locations, respectively. Current use of systemic (≥81.2%) and topical ( ≥74.7%) therapies was common, irrespective of lesion location. Disease severity increased with number of lesion locations: mean total BSA (ES = 1.17), EASI (ES = 1.11), and SCORAD (ES = 1.21). vIGA‐AD ≥3 was observed in 28.3%, 45.3%, 78.0%, and 93.9% of patients with 1, 2–3, 4–6 and ≥7 locations, respectively (ES = 0.63). Greater number of lesion locations was associated with worse PROs: mean POEM (ES = 0.57), sleep loss (ES = 0.41), peak pruritus (ES = 0.50), DLQI (ES = 0.40), and ADCT (ES = 0.53). Uncontrolled AD (ADCT ≥7) was observed in 48.2%, 52.9%, 70.4%, 81.6% of patients with 1, 2–3, 4–6 and ≥7 locations, respectively (ES = 0.42).ConclusionsAD lesions were reported for each body area assessed. Greater number of lesion locations was associated with increased disease severity, poor disease control, and decreased quality of life. Patients experienced substantial disease burden regardless of number of lesion locations involved.

Potential functionality of Cutibacterium acnes extracellular vesicles in atopic dermatitis and acne vulgaris: A comparative proteomic analysis.

Cutibacterium acnes is a commensal bacterium residing in healthy skin and plays a critical role in maintaining skin homeostasis. C. acnes has been considered closely related to acne vulgaris, while recent studies suggest that C. acnes and its metabolites may have a protective role in atopic dermatitis (AD) by modulating the immune system and maintaining skin homeostasis. Extracellular vesicles (EVs) are small membranous vesicles secreted by bacteria that participate in bacteria-host interactions. This study first compared C. acnes EVs from AD lesions (AD-EVs), acne lesions (Acne-EVs), and healthy skin (NC-EVs), using Label-free quantitative LC-MS/MS and validated differently expressed proteins by parallel reaction monitoring (PRM). Then Normal Human Epidermal Keratinocytes (NHEK) and human primary keratinocytes (KC) were treated with C. acnes EVs isolated from different groups, and the expressions of inflammatory factors were measured by quantitative real-time PCR and Western blotting. Compared with the acne group, the AD group showed greater downregulation of proteins related to energy metabolism and carbon source utilization pathway. Differences in protein profile in AD and acne lesion-separated C. acnes EVs correspond to the abnormal sebum secretion pattern in both diseases. C. acnes EVs from different groups affected different expressions of Th1 and Th2 inflammatory factors and epidermal barrier markers in NHEK and KC, indicating different immunomodulatory potentials. This study observed distinct proteomic differences between AD-EVs and Acne-EVs, and provided insights into the functional differences of C. acnes EVs in AD and acne.

Inhibition of RNase 7 by RNase inhibitor promotes inflammation and Staphylococcus aureus growth: Implications for atopic dermatitis.

The antimicrobial ribonuclease RNase 7 is abundantly expressed in the epidermis of lesional skin of atopic dermatitis (AD). Host RNase inhibitor (RI) binds to RNase 7 and blocks its ribonuclease activity. This study aimed to evaluate the impact of RNase 7-RI interactions on AD. Cultured human primary keratinocytes, with siRNA-mediated downregulation of RNase 7 and RI, were stimulated with the synthetic RNA polyinosinic-polycytidylic acid (poly I:C). Induction of proinflammatory mediators was analyzed by real-time PCR and ELISA. RI expression in AD non-lesional and lesional skin biopsies and healthy controls was analyzed by real-time PCR and immunostaining. RI protein release invivo on the AD skin surface was determined by western blot. Antimicrobial and ribonuclease assays were used to investigate the functional role of RI. RNase 7 inhibited the RNA-induced expression of proinflammatory mediators in keratinocytes. Accordingly, downregulation of RNase 7 in keratinocytes enhanced RNA-mediated induction of proinflammatory mediators, whereas downregulation of RI had the opposite effect. RI was released by damaged keratinocytes and epidermis. Invivo expression and release of RI on the skin surface were enhanced in lesional AD skin. Rinsing solution from the surface of lesional AD skin blocked the ribonuclease activity of RNase 7. The anti-Staphylococcus aureus activity of RNase 7 was abrogated by RI. Our data suggest a novel role of RI as a trigger factor of inflammation in AD by blocking the ribonuclease and antimicrobial activity of RNase 7, thereby enhancing RNA-mediated inflammation and S. aureus growth.

New Topical Treatment for Atopic Dermatitis

The primary approach for managing atopic dermatitis (AD) involves the use of topical corticosteroids as the first-line treatment.While high-potency topical corticosteroids have shown to be effective, they come with an increased risk of local and, rarely, systemic adverse effects. Additionally, patients often experience a relapsing and remitting course. A revolutionary topical treatment for psoriasis and AD has recently received patent approval from the Spanish Ministry of Industry, Trade, and Tourism. This innovative treatment, presented in the form of a lotion, includes a combination of clobetasol, papaverine hydrochloride, spironolactone, a milk-peptide complex, and propylene glycol. An 18-year-old female presented with AD on the back of her neck and scalp. The patient had no significant past medical history and primarily complained of intense pruritus in the AD lesions. The patient received guidance to apply our recently patented lotion, Psorisbye, once a day for 5 days. In total, 50 ml of Psorisbye was utilized over 4 days. On the fifth day, the patient underwent an examination at the outpatient clinic. The patient reported a significant improvement in pruritus sensations and observed a reduction in scaled lesions. Upon evaluating our patient, a comparison of the lesions before and after applying the topical treatment for 4 days revealed a notable improvement in the SCORAD index, decreasing from 49.95 to 0. While the results of Psorisbye in this case show promise, it is crucial to conduct further studies with larger sample sizes and extended follow-up periods to validate the findings presented in our case report.