Ovol1 regulates psoriasis-like skin inflammation and epidermal hyperplasia
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ABSTRACT:
PROVIDER: PRJNA670225 | ENA |
REPOSITORIES: ENA
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Project description:Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here we show that the expression of Ovol1 transcription factor is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod (IMQ). Using bulk and single-cell RNA-sequencing, we identify molecular changes in the epidermal, fibroblast and immune cells of Ovol1-deficient skin that reflect altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1 signaling in the microenvironment of IMQ-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for Ovol1 in curtailing psoriasis-like inflammation and the associated skin pathology
2021-12-01 | GSE159704 | GEO
Project description:Skin constitutes the outer permeability barrier that protects the body from dehydration and a myriad of external assaults. Epidermal keratinocytes act as the first line of innate immune defense, and barrier defects underlie common inflammatory skin diseases. However, the molecular mechanisms that maintain barrier integrity when skin is under challenge to regulate the interplay between epidermal and immune cells are not fully understood. Here we report upregulated expression of transcriptional repressorencoding Ovol1 in epidermal cells of inflamed skin, and its functional importance in maintaining barrier integrity of physically or chemically challenged skin. Following stimulation with imiquimod, Ovol1-deficient mice exhibit significantly aggravated epidermal hyperplasia and psoriasis-like skin inflammation featuring persistent neutrophil accumulation. Using bulk and single-cell RNA-sequencing, we characterize molecular changes in epidermal, fibroblasts, and immune cells that reflect altered epidermal proliferation and differentiation and/or significantly enhanced inflammatory responses as consequences of Ovol1 deletion. We identify both proliferation/differentiation-regulating and neutrophil-attracting chemokine genes as candidate direct targets of Ovol1. Finally, we provide evidence for altered IL-1a signaling in the microenvironment of Ovol1- deficient inflamed skin that functionally contributes to neutrophil accumulation and epidermal hyperplasia. Collectively, our study demonstrates a protective role for an epidermally expressed, disease-linked transcription factor in coordinating robust barrier maintenance with suppression of skin inflammation.
2021-10-27 | GSE158112 | GEO
Project description:Epidermal hyperplasia, a characteristic feature of psoriatic skin lesions, is epigenetically driven by Enhancer of Zeste homolog 2 (EZH2). EZH2 and EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) are both abnormally upregulated in psoriatic lesions. To identify microRNAs that could potentially target these epigenetic regulators we profiled miRNAs from psoriatic lesional skin in comparison with healthy skin. Analysis of the differentially expressed miRNAs revealed miR-101, as one of the most significant miRNA, consistently downregulated in psoriatic lesions compared to the healthy skin. A clear inverse correlation in the expression of miR-101 versus EZH2 was apparent in normal skin versus psoriatic lesional skin indicating that EZH2 is a potential target of miR-101, which was further confirmed by luciferase assay. Investigating the upstream effectors of the miR-101- EZH2 pathway in psoriasis, we identified the pro-inflammatory cytokine IL-17 as regulator of miR-101 expression. Here we propose a model, depicting a pathway triggered by IL-17 – mediated modulation of miR-101 expression, which in turn elicit sustained expression of EZH2, leading to enhanced keratinocyte proliferation and epidermal hyperplasia in psoriasis. Taken together, this indicates that miR-101 is a potential therapeutic target to alleviate the downstream effects of IL-17 mediated epidermal hyperplasia in psoriasis.
2023-09-19 | GSE220586 | GEO
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:Pla2g2f is dominantly expressed in the suprabasal layer of mouse epidermis. Microarray gene profiling supported the overall tendency of epidermal and sebaceous gland hyperplasia as well as alopecia in Pla2g2f-transgenic skin.
2015-08-08 | GSE71829 | GEO
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.
2013-12-10 | GSE50790 | GEO
Project description:Pla2g2f is dominantly expressed in the suprabasal layer of mouse epidermis. Microarray gene profiling supported the overall tendency of epidermal and sebaceous gland hyperplasia as well as alopecia in Pla2g2f-transgenic skin. Pla2g2f-Tg/+ mice and littermate controls (C57BL/6 background); 25-day old; skin; pooled from 4 mice for each genotype.
2015-08-08 | E-GEOD-71829 | biostudies-arrayexpress
Project description:Using lineage-tracing in a well-established psoriasis-like mouse model with inducible epidermal deletion of c-Jun and JunB, we found that mutant HF-SCs survive and express a broad group of pro-inflammatory cytokines, whereas mutant inter-follicular epidermal cells (IFE) disappear over time. Mutant HF-SCs initiate epidermal hyperplasia and skin inflammation by priming neighboring non-mutant epidermal cells to acquire a psoriasis-like phenotype. To explore the molecular mechanisms that govern the behavior of these distinct mutant and non-mutant HF-SCs and IFE cell populations during psoriasis-like disease, RNA sequencing analyses of sorted GFP+, Tomato+ HF-SCs and b-KCs from DKO*-mT/mG mice.
2019-08-23 | GSE119762 | GEO
Project description:Microarray gene profiling of skin from PLA2G10-Tg mice in comparison with that from control mice yielded data for explaining the overall tendency of Tg skin to show hair follicle distortion and epidermal hyperplasia associated with hyperkeratosis in the absence of inflammation
2015-08-08 | GSE71827 | GEO
Project description:Psoriasis is a complex inflammatory disease resulting from the activation of T helper (Th) 1 and Th17 cells. Recent evidence suggests that abnormal activation of Toll-like receptors (TLRs) 7, 8 and 9 contributes to the initiation and maintenance of psoriasis. We have evaluated the effects of TLR antagonists on the gene expression profile in an IL-23-induced skin inflammation model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the dorsum. Two TLR antagonists were compared: IMO-3100, an antagonist of TLRs 7 and 9, and IMO-8400, an antagonist of TLRs 7, 8 and 9, both of which previously have been shown to reduce epidermal hyperplasia in this model. Skin gene expression profiles of IL-23-induced inflammation were compared with or without TLR antagonist treatment. IL-23 injection resulted in alteration of 5100 gene probes (fold change ≥ 2, FDR < 0.05) including IL-17 pathways that are up-regulated in psoriasis vulgaris. Targeting TLRs 7, 8 and 9 with IMO-8400 resulted in modulation of more than 2300 mRNAs while targeting TLRs 7 and 9 with IMO-3100 resulted in modulation of more than 1900 mRNAs. Both agents strongly decreased IL-17A expression (>12-fold reduction), normalized IL-17 induced genes such as beta-defensin and CXCL1, and normalized aberrant expression of keratin 16 (indicating epidermal hyperplasia). These results suggest that IL-23-driven inflammation in mouse skin may be dependent on signaling mediated by TLRs 7, 8, and 9 and that these receptors represent novel therapeutic targets in psoriasis vulgaris and other diseases with similar pathophysiology. Expression profiles for mice with IL23-induced phenotype (psoriasisform) at baseline and after treatment with two doses of TLR7/8/9 antagonist and saline. Samples for nomal mice are also available
2014-01-21 | E-GEOD-50400 | biostudies-arrayexpress