MAS-related GPR family member X2-mediated mast cell activation promotes early inflammatory reaction in psoriasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Songmei Geng
PROVIDER: PXD047735 | iProX | Tue Dec 12 00:00:00 GMT 2023
REPOSITORIES: iProX
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Project description:Total protein of psoriasis skin samples was collected and dilution to 1 ml. 1 μg Recombinant Human GPCR MRGX2 protein (GST tag, Abcam, Cambridge, UK) was added into the protein solution, rotate for 4 h at room temperature. Then the anti-GST magnetic bead (BD, New Jersey, USA) was used for get the binding protein of MRGPRX2. Polypeptide segments were detected by liquid chromatography-mass spectrometry. Moreover, the Targeted Proteomics was used to prove BD1, BD3, LL-37, S00A9 and S100A6 (n=3).
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Project description:The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the contribution of IL-17 family cytokines other than IL-17A to drive skin inflammation in psoriasis has not been fully established. To further elucidate the role of individual IL-17 family cytokines in psoriasis, we investigated their expression and localization in psoriasis skin at the mRNA and protein level. Moreover, we investigated the gene expression signatures induced by individual IL-17 family cytokines in human skin ex vivo as well as modulation of responses induced by the combination of IL-17 family cytokines in human keratinocytes by brodalumab, a human monoclonal antibody targeting the IL-17RA, versus the IL-17A blocking antibody ixekizumab. We demonstrate that IL-17A, IL-17AF, IL-17F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce inflammatory gene expression signatures in human skin ex vivo that correlate with those observed in psoriasis. Furthermore, we show that brodalumab, in contrast to ixekizumab, fully blocks gene expression responses induced by the combination of IL-17A, IL-17AF, IL-17F and IL-17C in human keratinocytes. These findings suggest that inhibition of several IL-17 family cytokines, e.g. by targeting of the IL-17RA receptor, could be a favored mechanism to obtain a profound suppression of the inflammatory processes in psoriasis and thereby achieve high levels of skin clearance and sustained efficacy in patients with psoriasis.
2021-04-07 | GSE158448 | GEO
Project description:Herein we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n=3) were compared with littermate controls (n=3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average P = 0.0082; cystatin A, human orthologue); slc25a5 (average fold change of 46.2 and an average P = 0.0318); serpinb3b (average fold change of 35.6 and an average P = 0.0345; serpinB1, human orthologue); and kallikrein related peptidase 6 (average fold change of 4.7 and an average P = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, P < 0.0001), KLK6 (9.0-fold, P = 0.002), stefin A1 (7.3-fold; P < 0.001) and slc25A5 (1.5-fold; P = 0.05) using qRT-PCR on a second cohort of animals (n=8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; P < 0.05), 29,000-fold (stefinA1; P < 0.01), 322-fold (KLK6; P < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes vs. healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3.0-fold), KLK6 (5.8-fold) and serpinB1 (76-fold; all P < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover slc25a5, cystatin A, KLK6 and serpinB1 protein were all increased in lesional psoriasis skin compared to normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.
2014-10-30 | PXD001387 | Pride
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Project description:Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis on other skin areas. We sought to determine the cellular and mollecular phenotype of scalp psoriasis by performing a comparative analysis of scalp vs skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement, and 10 control subjects without psoriasis. Our results suggest that even in the scalp psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprinting were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with skin psoriasis which was mainly associated with activation of TNFâµ/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes. To define the transcriptomic profile of scalp skin, punch biopsies (6 mm diameter) were obtained from 20 Caucasian patients with untreated moderate to severe psoriasis with significative scalp involvement and 10 control subjects without psoriasis (N). Lesional (LS) samples were isolated from the infiltrated border of a plaque of psoriasis. Non lesional (NL) samples were taken from scalp areas with no visible psoriasis between the infiltrated plaques.
2015-11-25 | E-GEOD-75343 | biostudies-arrayexpress
Project description:Epigenetics plays a role in the pathogenesis of psoriasis vulgaris and generalized pustular psoriasis (GPP) through DNA methylation modifications that cause changes in immune responses. Psoriasis vulgaris is dominated by autoimmune responses, driven by Th17 cells producing IL-17, whereas GPP is dominated by autoinflammatory responses resulting from IL-36 dysregulation and neutrophil hyperactivation. Objective: This study aims to determine the DNA methylation profile and analyze the differences in IL-17 and IL-36 levels in both psoriasis phenotypes and healthy controls. Method: This study employed a cross-sectional design, comprising 20 patients with psoriasis vulgaris, three patients with GPP, and 13 healthy controls. DNA methylation profiles were assessed using Reduced Representation Methylation Sequencing, while IL-17 and IL-36 levels were assessed using ELISA. Results: Increased 5-methyl cytosine (5mC) was identified in psoriasis vulgaris and GPP compared to healthy controls. Increased 5mC at the FOXP3 promoter was identified in GPP and psoriasis vulgaris with high IL-17 levels, while decreased 5mC at the CARD14 promoter was identified in psoriasis vulgaris with high IL-17 levels. GPP showed higher IL-17 levels than healthy controls (p<0.05). IL-17 levels in psoriasis vulgaris showed no significant difference compared to GPP and healthy controls (p>0.05). IL-36 levels did not differ significantly among the three groups, with the highest IL-36 levels observed in psoriasis vulgaris (p>0.05). Conclusion: Increased DNA methylation in the FOXP3 gene promoter is predicted to cause high IL- 17 levels in psoriasis vulgaris and GPP, while IL-36 levels are higher only in psoriasis vulgaris.
2025-08-07 | GSE304903 | GEO
Project description:Purpose: This study aimed to explore the mechanism of Celastrol in improving psoriasis through single-cell transcriptomics Methods: Supplementation with intragastric administration of celastrol in C57BL/6 mice to observe its effect on IMQ-induced psoriasis. Single-cell RNA sequencing were performed to explore the role of celastrol for IMQ-induced psoriasis. Results: A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells Conclusion: We report that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages. The use of celastrol maybe a noveltherapeuticoption for psoriasis.
2024-04-20 | GSE231728 | GEO
Project description:Background: Psoriasis is a systemic inflammatory disease primarily affecting the skin. Approximately one-third of psoriasis patients develop joint involvement and are diagnosed with psoriatic arthritis (PsA). While, inIn adult-onset disease, adults, the development of arthritis usually follows skin psoriasis, but approximately 15% experience arthritis first, which can delay diagnosis. While the pathophysiology of psoriasis and PsA is incompletely understood, epigenetic dysregulation affecting CD4+ and CD8+ T-cells has been suggested. Objectives: This project aimed to identify disease-associated DNA methylation signatures in CD4+ T-cells from psoriasis and PsA patients that may be used as diagnostic and/or prognostic biomarkers. Methods: PBMCs were collected from 12 patients with chronic plaque skin psoriasis and 8 PsA patients, and 8 healthy controls. CD4+ T-cells were separated through FACS sorting, and DNA methylation profiling was performed (Illumina EPIC850K arrays). Bioinformatic analyses, including gene ontology (GO) and KEGG pathway analysis, were performed using R software. To identify genes under the control of interferon (IFN), the Interferome database was consulted, and DNA Methylation Scores were calculated. Results: Numbers and proportions of CD4+ T-cell subsets (naïve, central memory, effector memory, CD45RA re-expressing effector memory cells) did not vary between controls, skin psoriasis and PsA patients. 883 differentially methylated positions (DMPs) affecting 548 genes were identified between healthy controls and “all” psoriasis patients. Principal component and partial least-squares discriminant analysis separated controls from skin psoriasis and PsA patients. GO analysis considering promoter DMPs delivered hypermethylation of genes involved in “regulation of wound healing, spreading of epidermal cells”, “negative regulation of cell-substrate junction organization” and “negative regulation of focal adhesion assembly”. Comparing controls and “all” psoriasis, a majority of DMPs mapped to IFN-related genes (69.2%). Notably, DNA methylation profiles also distinguished skin psoriasis from PsA patients (2,949 DMPs/1,084 genes) through genes affecting “cAMP-dependent protein kinase inhibitor activity” and “cAMP-dependent protein kinase regulator activity” (GO analysis). Treatment with cytokine inhibitors (IL-17/TNF) corrected DNA methylation patterns of IL-17/TNF-associated genes, and methylation scores correlated with skin disease activity scores (PASI). Conclusion: DNA methylation profiles in CD4+ T-cells discriminate between skin psoriasis and PsA. DNA methylation signatures may be applied for quantification of disease activity and patient stratification towards individualized treatment. The aim of this study was to identify disease-associated DNA methylation signatures in CD4+ T-cells from patients with psoriasis and PsA that may be used as diagnostic and/or prognostic biomarkers to inform treatment and care.
2023-09-14 | GSE236694 | GEO
Project description:Background: Psoriasis is a systemic inflammatory disease primarily affecting the skin. Approximately one-third of psoriasis patients develop joint involvement and are diagnosed with psoriatic arthritis (PsA). While, inIn adult-onset disease, adults, the development of arthritis usually follows skin psoriasis, but approximately 15% experience arthritis first, which can delay diagnosis. While the pathophysiology of psoriasis and PsA is incompletely understood, epigenetic dysregulation affecting CD4+ and CD8+ T-cells has been suggested. Objectives: This project aimed to identify disease-associated DNA methylation signatures in CD4+ T-cells from psoriasis and PsA patients that may be used as diagnostic and/or prognostic biomarkers. Methods: PBMCs were collected from 12 patients with chronic plaque skin psoriasis and 8 PsA patients, and 8 healthy controls. CD4+ T-cells were separated through FACS sorting, and DNA methylation profiling was performed (Illumina EPIC850K arrays). Bioinformatic analyses, including gene ontology (GO) and KEGG pathway analysis, were performed using R software. To identify genes under the control of interferon (IFN), the Interferome database was consulted, and DNA Methylation Scores were calculated. Results: Numbers and proportions of CD4+ T-cell subsets (naïve, central memory, effector memory, CD45RA re-expressing effector memory cells) did not vary between controls, skin psoriasis and PsA patients. 883 differentially methylated positions (DMPs) affecting 548 genes were identified between healthy controls and “all” psoriasis patients. Principal component and partial least-squares discriminant analysis separated controls from skin psoriasis and PsA patients. GO analysis considering promoter DMPs delivered hypermethylation of genes involved in “regulation of wound healing, spreading of epidermal cells”, “negative regulation of cell-substrate junction organization” and “negative regulation of focal adhesion assembly”. Comparing controls and “all” psoriasis, a majority of DMPs mapped to IFN-related genes (69.2%). Notably, DNA methylation profiles also distinguished skin psoriasis from PsA patients (2,949 DMPs/1,084 genes) through genes affecting “cAMP-dependent protein kinase inhibitor activity” and “cAMP-dependent protein kinase regulator activity” (GO analysis). Treatment with cytokine inhibitors (IL-17/TNF) corrected DNA methylation patterns of IL-17/TNF-associated genes, and methylation scores correlated with skin disease activity scores (PASI). Conclusion: DNA methylation profiles in CD4+ T-cells discriminate between skin psoriasis and PsA. DNA methylation signatures may be applied for quantification of disease activity and patient stratification towards individualized treatment. The aim of this study was to identify disease-associated DNA methylation signatures in CD4+ T-cells from patients with psoriasis and PsA that may be used as diagnostic and/or prognostic biomarkers to inform treatment and care.
2023-09-14 | GSE236695 | GEO
Project description:In the present study, we analyzed single-cell multi-omics data from psoriasis patients and healthy individuals and found that more fibroblast-macrophage communication was present in the dermis of psoriasis lesions, exacerbating psoriasis progression. A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells. Moreover, conditional knockdown of LRP1 by fibroblasts significantly improved psoriasis in mice, suggesting that LRP1 may be an important target for the treatment of psoriasis.
2024-03-31 | GSE230842 | GEO