Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dissociating fibrosis from inflammation in systemic sclerosis – the case of interleukin-17A

ABSTRACT: Objectives. Interleukin-17A (IL-17A) levels are increased in SSc skin and other organs but its role in fibrosis development is highly debated. Since epithelial cells are preferential targets of IL-17A, we aimed at investigating the role of IL-17A in the interactions between epidermis and dermis. Methods. Organotypic cultures of HD full human skin were challenged with IL-17A,TNF and TGF-β. Inflammatory mediators and type I collagen (col-I) levels were quantified. IL-17A- and TGF-β-induced changes in gene expression in full human skin were analysed by RNA sequencing. Results. In full human skin, TGF-β induced pro-fibrotic gene signature dominated by Wnt signalling. While IL-17A strongly promoted expression of many pro-inflammatory genes, it did not affect collagen gene levels but decreased Wnt signalling. At the protein level, IL-17A showed direct anti-fibrotic effects, as well as decreased by 2-fold TGF-β-triggered col-I production. Conclusions. We report here firstly, a novel model of fibrotic skin and secondly, that IL-17A acts as a potent anti-fibrotic factor in the full human skin. Furthermore, we show that IL-17A not only decreased ECM deposition by itself, but also counteracted TGF-β pro-fibrotic activities. Thus, IL-17A seems to play a dual role in SSc skin – strongly pro-inflammatory but anti-fibrotic, being an example that fibrosis and inflammation, although closely related, are two different processes. These data may help in directing and interpreting therapeutic approaches in SSc, since both, IL-17A and TGF-β, are target candidates in clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122305 | GEO | 2020/02/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Whole-genome microarray analysis of human skin fibroblasts

Project description:Connective tissue growthfactor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor-beta (TGF-beta) and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We have previously shown that keratinocytes in vitro downregulate TGF-beta induced expression of CTGF in fibroblasts by an interleukin-1 alfa (IL-1alfa) dependent mechanism. With this study we want to get a better overall perspective who fibroblasts respond on TGF-beta and in a TGF-Beta stinulated system, what effect addition of IL-1 alfa have. This to understand the expression of CTGF in human fibroblasts which in turn have implications for the pathogenesis of fibrotic conditions involving the skin. Microarray was performed on human skin fibroblast RNA from one patient, Fibroblasts were seeded in vitro as a control (Control, C), TGF-beta were added to fibroblasts and incubated for 16 h (addition of TGF-beta, T) and both IL-1alfa and TGF-beta were added to fibroblasts for 16 h (addition of IL-1alfa and TGF-beta, IT). Each condition (C,T and IT) were done in three replicates.

2016-04-14 | E-GEOD-69447 | biostudies-arrayexpress

Whole-genome microarray analysis of human skin fibroblasts

2016-04-14 | GSE69447 | GEO

Transcription profiling of lesional and non-lesional skin from acne patients to study the role of inflammation in early acne lesions

Project description:The mechanisms of inflammation in acne are not well understood. This study performed in two separate patient populations focused on the activation of adaptive and innate immunity in early inflamed acne. Biopsies were collected from lesional and non-lesional skin of acne patients. Psoriasis patients and healthy volunteers were included in the study for comparison (not included in the records). Using Affymetrix Genechips, we observed significant elevation of the signature cytokines of the Th17 lineage in acne lesions compared to non-lesional skin. The increased expression of IL-17 was confirmed with real-time qPCR (RT-PCR) in two separate patient populations. Cytokines involved in Th17 lineage differentiation (IL-1beta, IL-6, TGF-beta; IL23p19) were remarkably induced at the RNA level. In addition, pro-inflammatory cytokines (IL-8, TNF-α), Th1 markers (IL12p40, CXCR3, T-bet, IFN-gamma), T regulatory cell markers (Foxp3, IL-10, TGF-β) and antimicrobial peptides (S100A7, S100A9, LNC2, hBD2, hBD3, hCAP18) were induced. Importantly, immunohistochemistry revealed significantly increased numbers of IL-17A positive T cells and CD83 dendritic cells in the acne lesions. In summary our results demonstrate the presence of IL17A positive T cells and the activation of Th17-related cytokines in acne lesions, indicating that the Th17 pathway may play a pivotal role in the disease process, offering new targets of therapy. Total of 24 chips. 12 patients : 2 biospies per patient: 1 lesional and 1 non lesional.

2014-09-25 | E-GEOD-53795 | biostudies-arrayexpress

Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis

Project description:Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs act as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs.

2023-12-06 | GSE249279 | GEO

IL-25 participates in keratinocyte-driven dermal matrix turnover and is reduced in Systemic Sclerosis epidermis

Project description:Aberrant deposition of extracellular matrix (ECM) resulting in dermal fibrosis is a hallmark of systemic sclerosis (SSc). Evidence suggests that dysfunctional SSc keratinocytes may contribute to fibrosis by altering dermal homeostasis. Whether interleukin-25 (IL-25), an IL-17 family member involved in epithelial/mesenchymal/immune cell interplay takes part in skin fibrosis is unknown. Here we address the role of IL-25 in SSc skin fibrosis. Compared to healthy donor (HD), in SSc and scleroderma-like disorders the epidermis expressed significantly lower levels of IL-25. In epidermal equivalents, IL-25 regulated several molecular pathways related to wound healing and ECM remodeling. Compared to control conditioned medium (CM), the CM from IL-25-primed keratinocytes enhanced the production by fibroblasts of matrix metalloproteinase-1 (MMP-1), IL-6, IL-8 (p< 0.05), but not of type-I collagen (Col-I ) nor fibronectin. However, IL- 25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. These results show that IL-25 participates to skin homeostasis and its decreased expression in SSc may contribute to skin fibrosis by favoring ECM deposition over degradation.

2022-03-31 | GSE168312 | GEO

Gene expression profile of human epidermal keratinocytes in response to IFNgamma, IL-4, IL-6, IL-17A and IL-22

Project description:To understand the role of epidermal keratinocytes in immunopathology of skin diseases with predominant T helper (Th) cell responses, we measured the genome-wide transcriptional profile of human keratinocytes in response to IFNgamma, IL-4, IL-17A or IL-22, major cytokines produced by Th1, Th2, Th17 or Th22 cells, respectively. IL-6 was also included in the transcriptional profile analysis because a variety of pro-inflammatory stimuli stimulate human keratinocytes to produce IL-6 that has an autocrine or paracrine role in epidermal immunity. We aimed to discover commonly expressed genes in human keratinocytes in response to pro-inflammatory cytokines, which would be associated with common pathophysiological responses in various skin diseases such as skin permeability barrier disruption or epidermal hyperplasia. Normal human keratinocytes (NHKs) were stimulated with IFNγ, IL-4, IL-6, IL-17A and IL-22 for 24 hours and harvested for total RNA extraction and hybridization on Affymetrix microarrays.

2014-10-02 | E-GEOD-53751 | biostudies-arrayexpress

Ubiquitin Proteomics Analysis of Systemic Sclerosis Lung Fibroblasts with or without KLHL42 knockdown

Project description:Systemic scleroderma (SSc) is an autoimmune disease which results in fibrotic production in the lung. Resultant SSC-pulmonary fibrosis is the main cause of mortality among SSc patients. From high throughput RNAi screening, we uncovered the ubiquitin E3 ligase KLHL42 as a potential pro-fibrotic mediator of TGFb-dependent fibrotic signaling in primary SSc lung fibroblasts. In this analysis, we sought to uncover putative substrates for KLHL42 by comparing SSc lung fibroblasts with control or KLHL42 siRNA prior to TGFb-treatment, lysis, and TUBE precipitation. The resultant pull-down was analyzed with LC-MS/MS.

2020-01-14 | MSV000084800 | MassIVE

The expression profiles of extracellular matrix-related genes in the presence or absence of IL-17A or -17F as measured with the PCR array in systemic sclerosis (SSc) dermal fibroblasts

Project description:We examined the effect of IL-17 signaling pathway on extracellular matrix (ECM) expression and the involvement of IL-17 signaling pathway in pathogenesis of SSc. To identify differences in the expression pattern of ECM genes in IL-17A- or IL-17F-treated cells, we performed PCR array analysis, consisting of 84 ECM-related genes. Normal human dermal fibroblasts were cultured until they were confluent, and then stimulated with IL-17A or IL-17F for 12 hours, and total RNA was extracted. A mixture of equal amounts of mRNAs from three normal fibroblasts was prepared in the presence or absence of IL-17A or -17F, and mRNA expression profile was evaluated using PCR Array. Normal fibroblasts were obtained by skin biopsies from 3 healthy donors. Fibroblasts from donors were used and treated separately as indicated in the summary. Equal amount total RNA from each donor was pooled prior to gene expression analysis.

2012-01-01 | E-GEOD-33581 | biostudies-arrayexpress

SOX11 promotes skin fibrosis by inducing fibrotic factors

Project description:In this study, we demonstrated that baseline SOX11 expression was significantly higher in dermal fibroblasts (DFs) isolated from patients with SSc than that in controls, and increased in response to TGF-b. We then showed that SOX11 is involved in the expression of periostin and some periostin-dependent fibrotic factors identified in lung fibroblasts previously. Moreover, we identified some fibrotic factors induced by SOX11 in DNA microarrays combining TGF-b induction and SOX11 knockdown. Finally, we showed that genetic deletion of SOX11 in Postn positive fibroblast cells protects from bleomycin (BLM)-induced skin fibrosis. Altogether, our data indicate that SOX11 and periostin forms a vicious circle and that TGF-b activates this circle specifically in SSc dermal fibroblasts.

2023-01-29 | GSE206473 | GEO

MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells

Project description:Systemic sclerosis (SSc) is a chronic autoimmune disease characterized with fibrosis of skin and multiple vital organs, but the immunological pathogenesis of SSc remains largely unknown. We show here that microRNA-19b (miR-19b) promotes IL-9-producing CD4+ T cells (Th9) that exacerbate SSc. Specifically, TGF-b plus IL-4 induced expression of TNF receptor associated factor 6 (TRAF6) through phosphorylated Smad3 linker region site Serine 213 (p-Smad3L-Ser213) and activated it through K63 ubiquitination by suppressing the leucine-rich-repeat-containing protein 3 (NLRC3). TRAF6 consequently formed complex with and activated TGF-b activated kinase 1 (TAK1). TAK1 promoted nuclear factor kappa B (NFκB) p65 activation, which then specifically upregulated miR-19b. miR-19b activated Il9 gene expression and promoted Th9 differentiation by directly targeting and suppressing atypical E2F family member E2f8 gene, a repressor for Il9 gene transcription. Importantly, Th9 cells played a critical role in the development and pathogenesis of experimental SSc by promoting the fibrosis in mice induced with Bleomycin. miR-19b and IL-9 were increased in CD4+ T cells in experimental SSc in mice and also in patients with SSc. Strikingly, inhibition of miR-19b resulted in fewer Th9 cells and attenuated fibrotic manifestations and ameliorated the disease in SSc mice. Our study identifies miR-19b as a key factor of Th9 cells that are involved in the pathogenesis of SSc. Our findings should have clinical implications for patients with SSc.

2024-08-21 | GSE269954 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data