Bulk RNA sequencing of skin biopsies from psoriasis patients treated with roflumilast or placebo
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1193084 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31573200_1.fastq.gz | Fastqsanger.gz | |||
| SRR31573200_2.fastq.gz | Fastqsanger.gz | |||
| SRR31573201_1.fastq.gz | Fastqsanger.gz | |||
| SRR31573201_2.fastq.gz | Fastqsanger.gz |
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Project description:This sub-study investigated the cellular and molecular effects of oral roflumilast treatment on psoriatic skin. Patients with moderate-to-severe psoriasis were allocated 1:1 to monotherapy with oral roflumilast 500 μg QD or placebo in a company-independent, randomized clinical trial (the PSORRO study, ClinicalTrials.gov NCT04549870).
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Project description:Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory thus a better understanding the pathogenesis of GPP is warranted. To assess the pathophysiological differences between GPP and PV we performed a gene expression study on formalin-fixed paraffin-embedded biopsies of GPP (n=30) and PV (n=12) lesions and healthy control (n=20) skin. Compared with healthy skin, GPP lesions yielded 365 and PV 898 differentially expressed genes respectively, with 190 upregulated in both diseases. We detected higher expression of IL-1 and IL-36 cytokines in GPP lesions compared with PV, and this occurred proximal to neutrophils. We show both activated neutrophils and isolated neutrophil proteases can activate IL-36. Diverging from the Th1/Th17 pathophysiology of PV, significantly fewer IL23A, IL17A, IFNG, CXCL9, CXCL10 and MX1 transcripts were detected in GPP lesions. Our data indicate a level of sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration and pustule formation, suggesting that the IL-1 and IL-36 inflammatory axes are the main drivers of disease pathology in GPP.
2017-01-27 | GSE79704 | GEO
Project description:Psoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN-gamma is involved in many cellular processes, including activation of T cells and dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN-gamma-producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN-gamma was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, important contributors to the inflammatory cascade in psoriasis lesions. To determine if IFN-gamma indeed induces the pathways leading to the development of psoriasis lesions, a single intradermal injection of IFN-gamma was administered to an area of clinically normal, non-lesional skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN-gamma induced molecular and histological features characteristic of psoriasis lesions. IFN-gamma increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products TNF, iNOS, IL-23, and TRAIL were present in IFN-gamma-treated skin. Thus, IFN-gamma, which is significantly elevated in non-lesional skin compared to healthy skin, appears to be a key pathogenic cytokine that can induce the inflammatory cascade in psoriasis. RNA was isolated from whole skin punch biopsies of either healthy or non-lesional psoraisis patients at baseline or 24 hours after placebo or IFN-g injection.
2011-11-30 | E-GEOD-32407 | biostudies-arrayexpress
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
Project description:Psoriasis is a chronic inflammatory skin disease characterized by marked proliferation of keratinocytes leading to pronounced epidermal hyperplasia, elongation of rete ridges and hyperkeratosis. The most common form of psoriasis, chronic plaque psoriasis (Psoriasis vulgaris), involves relatively stable occurrence and progression of sharply demarcated lesions, usually on the trunk and extremities, which share a combination of trademark histological features, including tortuous and dilated dermal capillaries, loss of the epidermal granular layer, and accumulation of neutrophils beneath parakeratotic scale. In this study, whole-genome transcriptional profiling was used to characterize gene expression in 4 lesional and uninvolved skin samples obtained from patients with stable chronic plaque psoriasis. Skin mRNA expression was analysed by microarray. Four individuals with chronic plaque psoriasis were enrolled. 6 mm punch biopsies were obtained under local anaesthesia (lidocaine) from uninvolved skin and a target plaque.
2013-12-10 | E-GEOD-50790 | biostudies-arrayexpress
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:Here we elucidate the molecular mechanism of tofacitinib, an oral Janus kinase inhibitor, in psoriasis. Tofacitinib exhibits a multi-tiered action, with early direct effects on keratinocytes and histological and transcriptomic improvement prior to IL-17 reduction. Twelve patients with plaque psoriasis were randomized (3:1) to receive tofacitinib 10Â mg or placebo twice daily for 12 weeks. Biopsies were taken from lesional and nonâlesional skin at baseline, and from lesional skin on Day 1, Day 3, and Weeks 1, 2, 4 and 12. Biopsies were examined for psoriatic epidermal features (thickness; Ki67+ keratinocytes, keratin 16 [KRT16] mRNA expression; phosphoSTAT [pSTAT] + nuclei) and T-cell and dendritic cell (DC) subsets using immunohistochemistry. mRNA transcripts were quantified by microarray.
2016-06-30 | E-GEOD-69967 | biostudies-arrayexpress
Project description:Biopsies from uninvolved and from lesional skin of 13 patients with plaque-type psoriasis. Based on paired samples, 179 genes were more than 2-fold differentially expressed in lesional skin. Experiment Overall Design: Comparative RNA expression profiles from uninvolved and lesional skin of 13 patients with mild to severe plaque-type psoriasis.
2008-11-07 | E-GEOD-6710 | biostudies-arrayexpress
Project description:Purpose: To identify the gene expression and upstream regulator at lesional skin of psoriasis vulgaris Methods:Full-thickness skin biopsies at lesional skin and uninvolved skin were taken from psoriasis patients. Transcriptomic profiling was constructed by high-throughput next-generation sequencing (NGS) technology Result:The total of 1328 DEGs are identified. Among these 1328 DEGs, 648 were upregulated and 680 were down regulated . Upstream regulators involving in keratinocyte proliferation was predicted to be activated. These DEGs and upstream regulator may be associated with psoriasis pathogenesis Conclusion: This study revealed upstream regulator that may be involved in psoriasis pathogenesis
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