Dupilumab-Mediated Modulation of Skin Barrier Proteomics
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Lin Ma
PROVIDER: PXD063362 | iProX | Sun Apr 27 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Background: Atopic dermatitis (AD) is characterized by skin barrier dysfunction. The impact of targeted therapies on skin barrier function and associated barrier protein changes remains not fully identified. Objective: To investigate the skin barrier function and proteomics in AD before and after different targeted therapies. Method: 15 healthy controls and 29 adult patients with moderate-to-severe AD were enrolled. AD patients were randomized into two groups. One group received dupilumab (N = 14) and the other received abrocitinib (N = 15). Clinical assessments and skin barrier parameters (transepidermal water loss [TEWL] and hydration) were measured at baseline, 4 weeks, and 12 weeks of treatment. Skin tape strips were collected for four-dimensional data-independent acquisition-based proteomics. Results: Both therapies improved skin barrier function, with abrocitinib showing greater effects on decreasing TEWL in the non-lesional skin. The proteomic analysis identified 1237 lesional and 785 non-lesional differentially expressed proteins (DEPs) between AD patients and healthy controls, especially in pathways related to ceramide metabolism, neurobiology, and keratinocyte biology. Treatment with abrocitinib resulted in more DEPs and significantly upregulated proteins associated with the epidermal barrier while downregulating immunological and itch-related proteins. It also increased key barrier proteins (filaggrin-2 and loricrin) in lesional skin, which was not shown in the dupilumab group. Both treatments regulated specific proteins in non-lesional skin, such as grancalcin and phospholipase D3. Conclusion: The study suggests that both targeted therapies improve the skin barrier function in AD, but they have different effects on barrier proteins, with abrocitinib having stronger effects.
2025-04-19 | PXD055561 | Pride
Project description:Barrier integrity is central to the maintenance of a healthy immunological homeostasis. Impaired skin barrier function is linked with enhanced allergen sensitization and the development of diseases such as atopic dermatitis (AD), which can precede the development of other allergic diseases such as food allergies and asthma. Epidemiological evidence indicates that children suffering from allergies have lower levels of dietary fibre-derived short-chain fatty acids (SCFA). Using an experimental model of AD, we report that a fermentable fibre-rich diet alleviates AD severity and systemic allergen sensitization. The gut-skin axis underpins this phenomenon through SCFA, which strengthen skin barrier integrity by altering mitochondrial metabolism of epidermal keratinocytes. SCFA promote keratinocyte differentiation and the production of key structural lipids, resulting in enhanced barrier function. Our results demonstrate that dietary fibre and SCFA mitigate AD by improving barrier integrity, ultimately limiting early systemic allergen sensitization and development of disease.
2022-08-24 | GSE185640 | GEO
Project description:Atopic dermatitis (AD) is a heritable inflammatory disease, characterised by skin barrier dysfunction. Genome-wide association studies (GWAS) have identified molecular targets with relevance for drug development, but the strongest genetic association, FLG, has not yet been successfully targeted in atopic disease. An AD-associated locus on chromosome 11q13.5 lies between two genes - EMSY and LRRC32 - but the functional mechanisms leading to AD are unclear. We applied a combination of genomic and molecular analytical techniques followed up in patient biopsies, to investigate pathomechanisms at this GWAS locus. Chromosome conformation capture data in keratinocytes shows interaction of the intergenic region in threedimensional space with EMSY. siRNA-mediated knockdown of EMSY in skin organoid culture leads to enhanced development of barrier function, measured by water evaporation and dye penetration. Global proteomic analysis of skin organoids with EMSY knockdown shows increased expression of structural and functional proteins, confirmed by histological and ultrastructural features. Lipid analysis shows an increase in ceramides known to be reduced in AD. Conversely, over-expression of EMSY in primary human keratinocytes leads to a reduction in biomarkers of barrier formation. Finally, skin biopsy samples from patients with AD show greater EMSY staining in the nucleus, consistent with increased functional effect of this DNAbinding protein. Together our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach for AD.
2019-06-24 | PXD014088 | Pride
Project description:Identifying children at risk of developing asthma is crucial in guiding targeted preventive therapies. In recent years, researchers have proposed several candidate biomarkers for predicting AM. One such biomarker is fatty-acid-binding protein 5 (FABP5), which correlates with interleukin-17A levels in both the skin and serum, suggesting its potential as a biomarker for AM. Specific IgE, skin prick tests, and cytokine ratios show promise in predicting asthma development.3 However, while these proposed biomarkers are the subject of research on the skin, no biomarkers are identified through blood proteomics. Although AD may initially result from skin barrier dysfunction, systemic sensitization and changes in systemic immune response may predominantly contribute to asthma after AD. Therefore, this study aims to identify blood biomarkers in early life to predict AM progression among infants initially diagnosed with AD. The study participants included 20 healthy controls, 15 with AD, 11 with asthma, and 21 with AM (children aged 7 years old). All participants were diagnosed with asthma, and a history of AD was confirmed by a physician. The protein expression profiles in plasma samples collected from 3-year-olds before the onset of AM were evaluated using sequential window acquisition of all theoretical mass spectra.
2025-05-06 | PXD050231 | Pride
Project description:Background: Atopic dermatitis (AD) is a common inflammatory skin disease exhibiting a predominantly Th2/"T22" immune activation and a defective epidermal barrier. Narrow-band UVB (NB-UVB) is considered an efficient treatment for moderate to severe AD. In psoriasis, NB-UVB has been found to suppress the Th1/Th17 immune polarization with subsequent reversal of epidermal hyperplasia. The immunomodulatory effects of this treatment are largely unknown in AD. Our study evaluates the effects of NB-UVB on immune and barrier abnormalities in AD, aiming to establish reversibility of disease and biomarkers of therapeutic response. Methods: 12 moderate-to-severe chronic AD patients received NB-UVB phototherapy 3 times weekly for up to 12 weeks. Lesional and non-lesional skin biopsies were obtained before and after treatment and evaluated by gene-expression and immunohistochemistry studies. Results: All patients had at least a 50% reduction in SCORing of AD (SCORAD) index with NB-UVB phototherapy. The Th2, T22, and Th1 immune pathways were suppressed and measures of epidermal hyperplasia and differentiation also normalized after phototherapy. The reversal of disease activity was associated with elimination of inflammatory leukocytes, Th2/"T22"-associated cytokines and chemokines, and normalized expression of barrier proteins. Conclusions: Our study shows reversal of both the epidermal defects and underlying immune activation in AD. By determining the correlation of variables with therapeutic response, we have defined a set of biomarkers of disease response that associate resolved Th2 and T22 inflammation with reversal of barrier pathology. This data supports the "inside-out" hypothesis of AD, suggesting that it is a disease primarily driven by an immune stimulus. genomic profiling of treatment effect of NB-UVB in AD in both lesional and non-lesional AD skin from 10 patients. Treatment effect, disease state analysis
2011-07-01 | E-GEOD-27887 | biostudies-arrayexpress
Project description:Background: Atopic dermatitis (AD) predominantly affects young children, but our understanding of AD pathogenesis is based on skin and blood samples from longstanding adult AD. Genomic biopsy profiling from early pediatric AD showed significant Th2 and Th17/Th22-skewing, without the characteristic adult Th1 up-regulation. Since obtaining pediatric biopsies is difficult, blood gene expression profiling may provide a surrogate for the pediatric skin signature. Objective: To define the blood profile and associated biomarkers of early moderate-to-severe pediatric AD. Methods: We compared microarrays and RT-PCR of blood cells from 28 AD children (<5yrs and within 6 months of disease onset) to healthy control blood cells. Differentially expressed genes/DEGs in blood (fold change/FCH>1.2 and false discovery rate/FDR<0.05) were then compared with skin DEGs. Results: Eosinophil and Th2 markers (IL5RA, IL1RL1/ST2, HRH4, CCR3, SIGLEC8, PRSS33, CLC from gene arrays; IL13/IL4/CCL22 from RT-PCR) were upregulated in early pediatric AD blood, while IFNG/Th1 was decreased. Th1 markers were negatively correlated with clinical severity (EASI, pruritus, transepidermal water loss/TEWL), whereas Th2/Th17-induced IL19 was positively correlated with SCORAD. While a few RT-PCR-defined immune markers (IL13/CCL22) were increased in blood, as previously also reported for skin, there was minimal overlap based on gene array DEGs. Conclusion: The whole blood signature of early moderate-to-severe pediatric AD blood cells show predominantly a Th2/eosinophil profile, but markers largely differ from the skin profile. Given their complementarity, pooling of biomarkers from blood and skin may improve profiling and predictions, providing insight regarding disease course allergic comorbidity development, and response to systemic medications.
2018-12-06 | GSE116486 | GEO
Project description:The skin barrier is vital for protection against environmental threats including insults caused by skin-resident microbes. Dysregulation of this barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While Malassezia is the most abundant commensal fungus of the skin, little is known about the host control of this fungus in inflammatory skin diseases. Here we show that in barrier-impaired skin, Malassezia acquires enhanced fitness and overt growth properties. By using four distinct and complementary murine models of atopic dermatitis and ichthyosis we provide evidence that structural and metabolic changes in the dysfunctional epidermal barrier environment provide increased accessibility and an altered lipid profile, to which the lipid-dependent yeast adapts for enhanced nutrient assimilation. These findings reveal fundamental insights into the implication of the mycobiota in the pathogenesis of common skin barrier disorders.
2024-02-20 | GSE253214 | GEO
Project description:To identify the effects of BJIKT on skin homoestasis via skin barrier, AhR target genes and the immune response profile in AD mice fed a low-Ahr ligand diet.
2023-08-21 | GSE226916 | GEO
Project description:The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in adaptive cell functions, and highly active in the epidermis. AhR-ligands can accelerate keratinocyte differentiation, but a precise role for AhR in the skin barrier is unknown. We here show that transepidermal water loss (TEWL), a parameter of skin barrier integrity, is high in AhR-deficient (AhR-KO) mice. Experiments with conditionally AhR-deficient mouse lines identified keratinocytes as the major responsible cell population for high TEWL. Electron microscopy showed weaker inter-cellular connectivity in the epidermis of keratinocytes in AhR-KO mice, and gene expression analysis identified many barrier-associated genes as AhR targets. Moreover, AhR-deficient mice had higher inter-individual differences in their microbiome. Interestingly, removing AhR-ligands from the diet of wild-type mice mimicked AhR-deficiency regarding the impaired barrier. Vice versa, re-addition of the plant-derived ligand indole-3-carbinol (I3C) rescued the barrier deficiency even in aged mice. Our results suggest that functional AhR expression is critical for skin barrier integrity and that AhR represents a molecular target for the development of novel therapeutic approaches for skin barrier diseases, including dietary intervention.
2016-08-31 | GSE80273 | GEO
Project description:Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. The goal of this study was to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared to skin from healthy controls and from lesional psoriasis skin. The aim was to identify differentially expressed genes involved in skin barrier formation and inflammation, and to compare our results with those reported for patients with moderate and severe AD. A total of 31 samples were analyzed: 8 healthy skin, 9 psoriatic plaques, 4 extrinsic AD lesional skin, 10 intrinsic AD lesional skin.
2016-03-08 | E-GEOD-75890 | biostudies-arrayexpress