Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA401825 | ENA |
REPOSITORIES: ENA
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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.
| PXD051868 |
Project description:Plasmacytoid dendritic cells (pDCs) detect microbial DNA via endosomal Toll-like receptor 9 (TLR9), yet the mechanisms by which they selectively internalize specific bacteria remain unclear. We demonstrate that type I interferon (IFN-I) responses to lactic acid bacteria (LAB) are entirely dependent on phagocytosis and exhibit pronounced strain specificity. Among tested strains, Lactococcus lactis strain Plasma (LC-Plasma) was efficiently phagocytosed and potently induced IFN-α in both primary human pDCs and CAL-1 cells, whereas closely related strains showed minimal uptake and cytokine production. Phagocytosis was essential for CD40 and CD86 upregulation as well as TLR9-dependent IFN-α secretion. Transcriptomic and functional analyses identified BDCA2, a galactose-binding C-type lectin receptor, as a key mediator of LAB uptake. Blocking BDCA2 significantly impaired both phagocytosis and cytokine responses. BDCA2-Fc fusion proteins bound strongly to LAB, and glycan profiling revealed enrichment of Galβ1-3GalNAc-containing glycans in highly phagocytosed Lactococcus strains. These findings define BDCA2-dependent phagocytosis as a critical determinant of strain-specific LAB recognition by human pDCs and highlight the role of surface glycan composition in modulating innate immune sensing.
2026-09-18 | GSE315830 | GEO
Project description:We show here that the antimicrobial peptide RNase 7 enables human pDCs to recognize self-DNA, and promotes their rapid sensing of bacterial DNA.
2017-09-07 | GSE103522 | 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: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: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
Project description:Plasmacytoid dendritic cells (pDCs) can be activated by the endosomal TLRs, and contribute to the pathogenesis of systemic lupus erythematosus (SLE) by producing type I IFNs. Thus, blocking TLR-mediated pDC activation may represent a useful approach for the treatment of SLE. In an attempt to identify a therapeutic target for blocking TLR signaling in pDCs, we investigated the contribution of Bruton's tyrosine kinase (Btk) to the activation of pDCs by TLR7 and TLR9 stimulation by using a selective Btk inhibitor RN486. Stimulation of TLR7 and 9 with their respective agonist, namely, gardiquimod and type A CpG ODN2216, resulted in the activation of human pDCs, as demonstrated by the expression of activation markers (CD69, CD40, and CD86), elevated production of IFN-alpha and other inflammatory cytokines, as well as up-regulation of numerous genes including IFN-alpha-inducible genes and activation of interferon regulatory factor 7 (IRF7) and NF-kB. RN486 inhibited all of these events induced by TLR9, but not TLR7 stimulation, with a nanomolar potency for inhibiting type A CpG ODN2216-mediated production of cytokines (e.g., IC50=386 nM for inhibiting IFN-alpha). Our data reveal Btk as an important regulatory enzyme in the TLR9 pathway, and a potential therapeutic target for SLE and other TLR-driven diseases. pDCs from healthy donors (n=4) were treated with gardiquimod (TLR7 agonist) or ODN 2216 (TLR9 agonist) with or without BTK inhibitor for 3 hours.
2015-10-24 | E-GEOD-41825 | 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.
2008-12-01 | GSE12218 | GEO
Project description:Dendritic cells (DCs) rely on Toll-like receptor 9 (TLR9) to detect unmethylated CpG motifs in microbial DNA, triggering essential immune responses. While the downstream signaling pathways of TLR9 activation are well characterized, their impact on S-palmitoylation is unknown. S-palmitoylation, involving the reversible attachment of palmitic acid to cysteine residues, plays a crucial role in regulating protein function and is catalyzed by the ZDHHC family of palmitoyl-acyltransferases (PATs). In this study, we investigated the S-palmitoylated proteome of bone marrow-derived GM-CSF DCs (GM-DCs) at resting and following TLR9 activation with CpGB. Using the click-chemistry compatible analog 17-octadecynoic acid (17-ODYA) and mass spectrometry-(MS)-based proteomics, we characterized dynamic remodeling of S-palmitoylation in response to TLR9 activation. This included enrichment of targets involved in immune and metabolic pathways. Transcriptomic analysis of mice and human DCs revealed TLR9-driven modulation of ZDHHC genes. Subsequently, we explored the contribution of ZDHHC9 to the regulation of S-palmitoylation in DCs. We found that Zdhhc9 deficiency affects the S-palmitoylation of specific proteins, revealing potential ZDHHC9 substrates. Interestingly, modulation of Zdhhc9 expression alone did not influence DC maturation, suggesting that other PATs might compensate for its activity. Together, our findings reveal a novel layer of regulation in TLR9 signaling mediated by S-palmitoylation.
2025-08-25 | PXD066223 | Pride
Project description:Plasmacytoid dendritic cells (pDCs) are a rare immune cell population that plays a key role in antiviral innate immunity. In our analysis, secretin (SCT) emerged as one of the most highly expressed hormones in both circulating and tissue-resident pDCs. To validate this finding, we performed spatial transcriptomic analysis of adult tonsil tissue, which demonstrated co-localization of SCT transcripts with the pDC marker LILR4A. We further confirmed SCT expression at the protein level by immunofluorescence staining of primary human peripheral blood pDCs, showing co-expression of secretin with the canonical pDC markers CLEC4C and TLR9. In a longitudinal single-cell RNA-sequencing dataset from individuals with COVID-19, we observed modest upregulation of SCT in interferon-activated pDCs. To determine whether SCT expression is linked to immune function, we purchased primary human peripheral blood pDCs and stimulated them in vitro with the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide, followed by single-cell transcriptomic profiling.
2026-05-22 | E-MTAB-16728 | biostudies-arrayexpress