Targeting of Th17-related cytokines in patients with Darier Disease
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ABSTRACT:
PROVIDER: PRJNA985620 | ENA |
REPOSITORIES: ENA
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Project description:Darier disease (DD) is a rare, inherited multi-organ disorder associated with mutations in the ATP2A2 gene. In DD patients, the skin is frequently affected, characterized by malodorous, inflamed skin and recurrent, severe infections. Therapeutic options are limited and inadequate for the long-term management of this chronic disease. Using immunoprofiling with NanoString technology, qPCR and immunohistochemistry, we demonstrate enhanced expression of Th-17-related genes and cytokines in six DD patients. We prove that targeting the IL-23/-17 axis in DD with monoclonal antibodies is an effective and safe therapy in DD patients, leading to significant clinical improvement. As DD is a chronic, relapsing disease, our findings provide new options for the long-term management of skin inflammation in patients with DD.
2023-09-25 | GSE235255 | GEO
Project description:Our data suggest that serum miR-204-3p has a potential as a useful biomarker among patients with FMF and that miR-204-3p plays a critical role as a suppressor to regulate the production of TLR4-related cytokines by targeting PI3K signaling pathway.
2017-06-01 | GSE98940 | GEO
Project description:Peripheral infections can result in neuropsychiatric changes in many contexts, including after recurrent Group A Streptococcus (GAS) infections in children. In a mouse model of intranasal GAS inoculation, we have previously demonstrated in vivo that mice lacking Th17 cells, or the key Th17 cytokines interleukin 17A (IL-17A) or granulocyte-macrophage colony-stimulating factor (GM-CSF), have altered microglial responses. As an attempt to determine whether these cytokines have direct effects on microglia, we cultured primary microglia and incubated them with either interferon gamma (IFNg), IL-17A or GM-CSF for 24 hours, then collected RNA for bulk sequencing. Microglia treated with IFNg or GM-CSF displayed striking transcriptional shifts, including upregulation of many inflammatory genes. IL-17A treatment did not have a noticeable effect on the microglial transcriptome, likely due to the in vitro absence of IL-17A receptors, which are expressed by microglia in vivo.
2023-03-14 | GSE221715 | GEO
Project description:Th17 cells are extensively studied because of their known pathogenic role in many inflammatory diseases, but are also important to support the integrity of the intestinal barrier in a non-inflammatory manner. Since therapeutic targeting of Th17 cell mediated pathologies carries the risk of inadvertently affecting protective Th17 cells, we set out to define the major distinctions between homeostatic tissue-resident Th17 cells and Th17 cells engaged in inflammatory reactions, focusing on the gut. We show here that homeostatic Th17 cells exhibit little plasticity towards expression of inflammatory cytokines, are characterised by a metabolism typical for quiescent or memory T cells, and do not participate in inflammatory processes. Infection-induced Th17 cells, on the other hand, show extensive plasticity towards pro-inflammatory cytokines, disseminate widely into the periphery and engage aerobic glycolysis in addition to oxidative phosphorylation typical for inflammatory effector cells.
2019-06-28 | GSE130302 | GEO
Project description:Effects of Th17 cytokines on transcriptome of primary microglial cultures in vitro
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Project description:Uncontrolled Th17 cell activity is associated with cancer and autoimmune and inflammatory diseases. To validate the potential relevance of mouse models of targeting the Th17 pathway in human diseases we used RNA sequencing to compare the expression of coding and non-coding transcripts during the priming of Th17 cell differentiation in both human and mouse. In addition to already known targets, several transcripts not previously linked to Th17 cell polarization were found in both species. Moreover, a considerable number of human-specific long non-coding RNAs were identified that responded to cytokines stimulating Th17 cell differentiation. We integrated our transcriptomics data with known disease-associated polymorphisms and show that conserved regulation pinpoints genes that are relevant to Th17 cell-mediated human diseases and that can be modelled in mouse. Substantial differences observed in non-coding transcriptomes between the two species as well as increased overlap between Th17 cell-specific gene expression and disease-associated polymorphisms underline the need of parallel analysis of human and mouse models. Comprehensive analysis of genes regulated during Th17 cell priming and their classification to conserved and non-conserved between human and mouse facilitates translational research, pointing out which candidate targets identified in human are worth studying by using in vivo mouse models. Altogether 114 (57 human and 57 mouse) samples were analyzed representing 3 biological replicates of timeseries data (0, 0.5, 1, 2, 4, 6, 12, 24, 48 and 72 hours) of Th17 polarized cells and control Th0 cells
2016-04-07 | E-GEOD-52260 | biostudies-arrayexpress
Project description:TGF-beta3 produced by developing Th17 cells induces highly pathogenic T cells that are functionally and molecularly distinct from TGF-beta1-induced Th17 cells. The microarray data represent a distinct molecular signature for pathogenic versus non-pathogenic Th17 cells. Total of seven groups with two to four samples per group from two independent experiments. The no cytokines group (Th0) was used as a control to normalize the data. 7 groups: B6: (IL-1beta, IL-6) B623: (IL-1beta, IL-6, IL-23) T16: (TGF-beta1, IL-6) T1623: (TGF-beta1, IL-6, IL-23) T36: (TGF-beta3, IL-6) T3623: (TGF-beta3, IL-6, IL-23) NOCYTO: no cytokines
2012-09-01 | E-GEOD-39820 | biostudies-arrayexpress
Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.
2020-05-26 | PXD010612 | Pride
Project description:Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we found that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cell cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of transcription factor NFκB and induction of IL 24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect in targeting IL-17A in uveitis.
2020-07-22 | GSE152534 | GEO
Project description:Purpose: Using RNA-sequencing, determine the effect of corticosteroids on human airway smooth muscle cells (ASM) exposed to Th1 and/or Th17 cytokines. Effects of cytokines and/or corticosteroids on gene expression was assessed. Methods: Pediatric human ASM (ages 0-21; n=4/treatment group) were serum starved for 48 h and then treated with 10 ng/mL TNFα, IFNγ, IL-17A, TNFα/IFNγ, or IFNγ/IL-17A in the presence of vehicle (0.01% DMSO) or 10 nM fluticasone propionate (FP). Cells were harvested after 18 h for RNA isolation, QC, library prep, and RNA sequencing on the Illumina HiSeq4000 platform. RNA quality and integrity was determined by gel electrophoresis and Agilent 2100 Bioanalyzer. Following sequencing. FASTQ files were processed and analyzed to generate counts files and perform differential expression analysis. Results: Our analyses show that cytokines, particularly TNFα, IFNγ, and TNFα/IFNγ had significant effects on gene expression. Differentially expressed genes were largely related to pro-inflammatory responses. Interestingly, we found that IL-17A had only modest effects on gene expression. Corticosteroids (FP) reduced or inhibited the effects of pro-inflammatory cytokines. However, these anti-inflammatory effects were reduced in cells treated with TNFα/IFNγ or IL-17A/IFNγ. Conclusions: These studies highlight the differential effects of pro-inflammatory cytokines and corticosteroids on gene expression in human ASM.
2022-05-25 | GSE179354 | GEO