Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA530390 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8835675.fastq.gz | Fastqsanger.gz | |||
| SRR8835676.fastq.gz | Fastqsanger.gz | |||
| SRR8835677.fastq.gz | Fastqsanger.gz | |||
| SRR8835678.fastq.gz | Fastqsanger.gz |
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Project description:To understand the overall function of IL-17RD and IL-17RC in IL-17A signaling, RNAseq was performed with WT, Il17rc KO, and Il17rd KO primary mouse keratinocytes following IL-17A treatment along with untreated WT control. Keratinocyte from neonatal WT, Il17rd KO, and Il17rc KO mice were cultured and stimulated with IL-17A (100 ng/mL, PeproTech) for 8h.
2019-04-17 | GSE129176 | GEO
Project description:To delineate mechanisms for psoriasis pathogenesis driven by the interleukin-17A, proteomic dysregulations were studied in a Human Primary Keratinocyte model system. Label-free quantification was performed and fold-changes were obtained for abundances of proteins in IL-17A treated keratinocytes versus those from IL-17A treated keratinocytes.
Briefly, Human Primary Keratinocytes were isolated and treated with the cytokine IL-17A (50ng/ml) in incomplete media devoid of any growth factors. Tryptic digested and desalted peptide samples were injected in Thermoscientific Q-Exactive Plus instruments through EasyNLC HPLC autosampler. The instruments were set to MS1 resolution of 70000 and MS2 resolution of 17500. The acquisition experiments were optimized to run on 120 min gradients.
The MS spectra were analyzed using the Thermoscientific mass informatics platform Proteome discoverer version 2.2. The common workflows for discovery proteomics were used with Mascot and SequestHT as search engines.
This dataset helped to simulate the IL-17A-driven inflammation in keratinocytes and uncovered many putative druggable targets in the context of psoriasis.
2022-08-11 | MSV000090116 | MassIVE
Project description:SARS-CoV-2 infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID19. The SARS-CoV-2 ORF8 is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 ORF8-deleted variants are associated with mild disease outcomes, but the molecular mechanism this behind is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expressions for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study discovers SARS-CoV-2 ORF8 as a viral mimicry of IL-17 cytokine to contribute COVID-19 severe inflammation.
2022-03-11 | GSE196455 | GEO
Project description:IL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. We used microarrays analysis to understand the impact of IL-17A on human monocyte-derived human dendritic cells. We found overexpression of many genes involved in lipid metabolism in IL-17A-treated dendritic cells compared to untreated dendritic cells. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. RNA was extracted from untreated in vitro-generated DC at day 0 (DC, 4 biological replicates ) or DC cultured for 12 days with IL-17A, in the absence or presence of IFN-g (DC-17 and DC-G17, 5 biological replicates)
2015-03-31 | E-GEOD-53163 | biostudies-arrayexpress
Project description: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.
2020-02-11 | GSE122305 | GEO
Project description:In psoriasis lesions, a diverse mixture of cytokines is upregulated which influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of Interleukin-17A (IL-17A) alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of 6 cytokines (IL-17A, TNF-a, IL-17C, IL-22, IL-36g and IFN-g) involved in psoriasis, to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A-regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on differences in the expression profiles of cells stimulated with 6 cytokines versus cells stimulated with only 5 cytokines lacking IL-17A. Furthermore a specific IL-17A-induced gene, NFKBIZ, which encodes IkappaB-zeta, a transcriptional regulator for NF-kappaB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis. Cytokine mixture-induced gene expression in primary normal human epidermal keratinocytes (NHEKs) was measured at 24 hours after exposure. NHEKs were exposed to the combination of selected six cytokines (IL-17A: 100 ng/ml, TNF-a: 10 ng/ml, IFN-g: 10 ng/ml, IL-17C: 100 ng/ml, IL-22: 100 ng/ml, IL-36g: 500 ng/ml) , or to the different combinations of five of the six cytokines (in total, 7 different treatments and one untreated control). No replicate experiments were conducted.
2016-03-08 | E-GEOD-77719 | biostudies-arrayexpress
Project description:Viral mimicry of Interleukin-17A by SARS-COV-2 ORF8
| PRJNA804953 | ENA
Project description:IL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. We used microarrays analysis to understand the impact of IL-17A on human monocyte-derived human dendritic cells. We found overexpression of many genes involved in lipid metabolism in IL-17A-treated dendritic cells compared to untreated dendritic cells. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases.
2015-03-31 | GSE53163 | GEO
Project description:The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6+ immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6+ cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.
| S-EPMC7072868 | biostudies-literature
Project description:In psoriasis lesions, a diverse mixture of cytokines is upregulated which influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of Interleukin-17A (IL-17A) alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of 6 cytokines (IL-17A, TNF-a, IL-17C, IL-22, IL-36g and IFN-g) involved in psoriasis, to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A-regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on differences in the expression profiles of cells stimulated with 6 cytokines versus cells stimulated with only 5 cytokines lacking IL-17A. Furthermore a specific IL-17A-induced gene, NFKBIZ, which encodes IkappaB-zeta, a transcriptional regulator for NF-kappaB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis.
2016-03-08 | GSE77719 | GEO