Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA288643 | ENA |
REPOSITORIES: ENA
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Project description:Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFN) and pro-inflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) played a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF-5 and IRF-8 on CpG dependent gene expression. Results from RNA interference and microarray studies indicate that IRF-5 up-regulates TLR9-driven gene expression whereas IRF-8 down-regulates the same genes. Several findings support the conclusion that IRF-8 inhibits TLR9 dependent gene expression by directly blocking the activity of IRF-5. First, the inhibitory activity of IRF-8 is only observed when IRF-5 is present. Second, proximity ligation analysis shows that IRF-8 and IRF-5 co-localize within the cytoplasm of resting human pDC and co-translocate to the nucleus after CpG stimulation. Taken together, these findings suggest that two transcription factors with opposing functions control TLR9 signaling in human pDCs.
2016-06-01 | GSE70429 | GEO
Project description:Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFN) and pro-inflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) played a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF-5 and IRF-8 on CpG dependent gene expression. Results from RNA interference and microarray studies indicate that IRF-5 up-regulates TLR9-driven gene expression whereas IRF-8 down-regulates the same genes. Several findings support the conclusion that IRF-8 inhibits TLR9 dependent gene expression by directly blocking the activity of IRF-5. First, the inhibitory activity of IRF-8 is only observed when IRF-5 is present. Second, proximity ligation analysis shows that IRF-8 and IRF-5 co-localize within the cytoplasm of resting human pDC and co-translocate to the nucleus after CpG stimulation. Taken together, these findings suggest that two transcription factors with opposing functions control TLR9 signaling in human pDCs. CAL-1 cells were transfected with siRNA targeting IRF-5 (IRF-5si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with siRNA targeting IRF-8 (IRF-8si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with control siRNA (Contsi) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats).
2016-06-01 | E-GEOD-70429 | biostudies-arrayexpress
Project description:we report that free cholesterol in the endolysosomal membrane regulates the IFN-I response in plasmacytoid dendritic cells (pDCs) by facilitating the release of TLR9 from UNC93B1.
2024-04-29 | PXD051868 |
Project description:To discover the key determinants of IRF-specific enhancer selection, we identified and characterized IRF binding regions. Using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq), we mapped the binding regions of IRF3, IRF5, and IRF9 in murine dendritic cells (DCs) stimulated with TLR3 and TLR9 agonists, as well as IFNβ, respectively. We comprehensively analysed the IRF cistromes to identify characteristic features, including DNA motifs for IRFs and other transcription factors, and chromatin status.
2019-07-31 | GSE125340 | GEO
Project description:Elevated cholesterol is positively associated with autoimmunity. However, it is unclear which mechanism directly link them. Here, we report that free cholesterol in the endolysosomal membrane regulates the IFN-I response in plasmacytoid dendritic cells (pDCs) by facilitating the release of TLR9 from UNC93B1. The cholesterol transporter NPC1 was highly expressed in pDCs, and conditional deletion of Npc1 via Cd11c-Cre (Npc1∆DC) impaired IFNα production by TLR9-stimulated pDCs. Npc1∆DC mice exhibited a weakened IFNα response to HSV-1 infection, and ameliorated anti-DNA autoantibodies and nephritis when crossed to B6.Sle1yaa transgenic lupus model. Mechanistically, through click chemistry-based proteome-wide screening, we found that the TLR chaperone UNC93B1 could bind to free cholesterol. The juxtamembrane cholesterol gradient, mediated by NPC1, promoted TLR9 release from UNC93B1. Increased membrane-bound cholesterol dramatically enhanced IFNα response by murine and human pDCs. Our results suggested that the participation of free cholesterol in TLR9 signaling could directly link elevated cholesterol with autoimmunity.
2025-01-18 | GSE253771 | GEO
Project description:RNase 7 strongly promotes TLR9-mediated DNA sensing by human plasmacytoid dendritic cells
| PRJNA401825 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE24726: Gene expression profile of mature plasmacytoid dendritic cells (PDC) after the deletion of transcription factor E2-2 GSE24740: Binding targets of transcription factor E2-2 in human plasmacytoid dendritic cells Refer to individual Series
2010-12-21 | E-GEOD-24785 | biostudies-arrayexpress
Project description:Robust type I interferon (IFN-alpha/beta) production in plasmacytoid dendritic cells (pDCs) is critical for anti-viral immunity. Here we demonstrated a role for the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or the ‘downstream’ mediators of mTOR p70S6K1,2 kinases during pDC activation via Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and the subsequent activation of interferon response factor 7 (IRF7), resulting in impaired IFN-alpha production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed anti-viral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in a diminution of IFN-alpha production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling plays a critical role in TLR-mediated IFN-alpha responses by pDCs. CpGA is a TLR9 agonist. pDCs were isolated from mouse spleen or human PBMC. The effect of rapamycin on pDCs IFN-alpha production as induced by TLR ligands was studied. The mechanism of rapamycin effect was dissected in RAW cell line.
2008-12-01 | E-GEOD-12218 | biostudies-arrayexpress
Project description:Type 1 interferons (IFNs) induce complex responses that can be beneficial or deleterious, depending on context. Greater understanding of the mechanisms of action of these cytokines could allow new therapeutic approaches. We found that type 1 IFNs induced changes in cellular metabolism that were critical for changes in target cell function. This was apparent in plasmacytoid dendritic cells, which are specialized for type 1 IFN production, where toll-like receptor-9 (TLR9)-dependent activation was found to be dependent on increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) induced by autocrine signaling through the type 1 IFN receptor (IFNAR). Type 1 IFNs also induced FAO/OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO/OXPHOS in virus-infected cells. Increased FAO/OXPHOS in response to IFNAR signaling was regulated by the nuclear receptor PPARα. Our findings reveal PPARα/FAO/OXPHOS as potential targets to therapeutically modulate downstream effects of type 1 IFNs. mRNA profiles of overnight stimulated plasmacytoid dendritic cells, activated with CpG or INFa. Samples analyzed in triplicate, with HiSeq 2500 byâ/ 50bpX25bp pair-end sequencing
2016-07-01 | E-GEOD-81889 | biostudies-arrayexpress
Project description:Autoantibodies against nucleic acids are a hallmark of Systemic Lupus Erythematosus. We recently uncovered that human oxidized DNA of mitochondrial origin released by activated lupus neutrophils represents a distinct class of interferogenic TLR9 ligand for plasmacytoid dendritic cells. We now show that oxidized mitochondrial DNA-activated plasmacytoid dendritic cells skew naïve CD4+ T cells towards IL2low, IFNγhigh, IL10high secreting B helper cells different from follicular helper and Type 1 regulatory CD4+ T cells. Furthermore, PD1-induced succinate and mitochondrial ROS accumulation revoke anergy, while IL10 and succinate synergize to deliver B cell help. We provide evidence that IL10-producing CD4+ T cells infiltrate the SLE kidney insterstitium, where they might play a role in extrafollicular B cell responses. Thus, we describe a novel B cell helper pathway that links innate and adaptive immunity alterations in human lupus.
2018-09-26 | GSE93679 | GEO