Mus musculus breed:C57BL6J
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA276738 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:IL-17 mediates immune protection from fungi and bacteria as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of LUBAC as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.
2020-07-15 | PXD019020 | Pride
Project description:The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. Specifically it has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that Th17 responses were augmented in the absence of T-bet, and we have defined a critical temporal window for T-bet function. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells. ChIP-seq analysis of T-bet in WT and Tbet -/- mice.
2013-12-03 | E-GEOD-40623 | biostudies-arrayexpress
Project description:IL-17 and IL-17R signaling in the intestinal epithelium regulate the intestinal microbiome. Given the reported links between intestinal dysbiosis, bacterial translocation, and liver disease, we hypothesized that intestinal IL-17R signaling plays a critical role in mitigating hepatic inflammation. To test this, we studied intestinal epithelial-specific IL-17RA deficient mice in a model of concanavalin A hepatitis. Absence of enteric IL-17RA signaling exacerbated hepatitis and hepatocyte cell death. These mice exhibited commensal dysbiosis, increased intestinal and liver Il18, and increased liver translocation of bacterial products, specifically CpG DNA. Mechanistically, CpG DNA induced hepatic IL-18, increasing IFNγ and FasL in hepatic T-cells to drive inflammation. Thus, intestinal IL-17R regulates translocation of TLR9 ligands and constrains susceptibility to hepatitis. These data connect enteric Th17 signaling and the microbiome in hepatitis, with broader implications on the effects of impaired intestinal immunity and subsequent release of microbial products seen in other extra-intestinal pathologies.
2019-12-10 | GSE128284 | GEO
Project description:RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells and an attractive drug target for treating Th17-associated diseases. Though the critical role of RORγt in early Th17 cell differentiation has been well recognized, whether it maintains mature Th17 cell phenotypes remains largely unexplored. Here, we show that genetic deletion of Rorc in mature Th17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin structure at key Th17-specific gene loci, particularly at those so called “super enhancer” regions. Furthermore, RORc deletion in effector Th17 cells resulted in a strongly Th2-biased cell phenotype at both epigenetic and transcriptional levels, in an IL-4-dependent manner. Our results thus reveal a crucial function of RORγt in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of RORγt.
2022-07-12 | GSE190538 | GEO
Project description:RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells and an attractive drug target for treating Th17-associated diseases. Though the critical role of RORγt in early Th17 cell differentiation has been well recognized, whether it maintains mature Th17 cell phenotypes remains largely unexplored. Here, we show that genetic deletion of Rorc in mature Th17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin structure at key Th17-specific gene loci, particularly at those so called “super enhancer” regions. Furthermore, RORc deletion in effector Th17 cells resulted in a strongly Th2-biased cell phenotype at both epigenetic and transcriptional levels, in an IL-4-dependent manner. Our results thus reveal a crucial function of RORγt in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of RORγt.
2022-07-12 | GSE190425 | GEO
Project description:The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. Specifically it has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that Th17 responses were augmented in the absence of T-bet, and we have defined a critical temporal window for T-bet function. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells.
2013-12-03 | GSE40623 | GEO
Project description:Intestinal IL-17R signaling controls liver inflammation by constraining microbiome-induced TLR9 signaling and IL-18 production
| PRJNA527218 | ENA
Project description:Calcineurin/NFAT/IL-2 signaling pathway is activated in dendritic cells (DC) upon encounter of β glucan, the main component of the fungal cell wall, raising the question about the role of NFAT-regulated genes in DC biology in vivo. To directly assess the function of IL-2 secreted by DC, we analyzed mice lacking of IL-2 in the DC lineage, CD4-expressing cells and with complete deletion of IL-2 in the germ line in a mouse model of pulmonary fungal infection. Here we found that specifically the loss of IL-2 in DC resulted in increased mice mortality upon the fungus Aspergillus fumigatus challenge and expansion of Th17 cells in the lung. We demonstrated that only CD103+DC were able to release IL-2 in acute phase of pulmonary Aspergillosis through the Ca2+-Calcineurin-NFAT signaling. We also found that NFAT mediates IL-23 transcription in lung DC, where IL-2 results essential in restraining the priming of a pathogenic infiltrating IL-17+Sca1+CD90+CD4+ cell with stem cell like properties. Thus, IL-2 and IL-23 secreted by DC in the lung have an antagonistic relationship on the Th17 differentiation program with IL-2 inducing T cell differentiation and IL-23 inducing a stem cell like molecular signature to Th17 cells upon Aspergillus challenge. DC-Il2-/- then confer the Th17 stemness, releasing IL-23 in response to the fungus contributing to the development of a Th17 cell effector population, particularly pathogenic in infection. D1 cells with no treatment, or treatment with different fungal types or antigens at 1, 4 and 6 hours, in triplicate, with the 3 untreated samples at 1hr also including techincal repeats
2015-12-21 | E-GEOD-58590 | biostudies-arrayexpress
Project description:Type 2 cytokine, interleukin (IL)-4 promotes the proliferation of adipocyte precursors and their commitment to the beige adipocyte lineage in white adipose tissue, which leads to the growth of beige fat and subsequent metabolic benefits. However, the underlying mechanism that mediates such context specific cell proliferation and lineage commitment is largely unknown and genome wide investigation has not yet been reported. Here, we performed the global analysis of gene expressions altered by IL4 stimulation in mouse adipocyte precursors through high-throughput sequencing of mRNAs and small RNAs.
2023-06-01 | GSE216077 | GEO