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Impaired activation of plasmacytoid dendritic cells via Toll-Like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift.

ABSTRACT: Plasmacytoid dendritic cells (pDCs) infiltrate a large set of human cancers. IFN-α produced by pDCs might induce growth arrest and apoptosis in tumor cells and modulates innate and adaptive immune cells involved in anti-cancer immunity. Moreover, pDC-derived effector molecules exert tumor cell killing. However, the activation state and clinical relevance of pDCs infiltration in cancer is still largely controversial. In Primary Cutaneous Melanoma (PCM), pDCs density decreases over disease progression and collapses in metastatic melanoma (MM). Moreover, the residual circulating pDC compartment is defective in IFN-α production. Here, based on a set of microscopic, functional and in silico analysis, we demonstrated that the melanoma secretome directly impairs type I interferon and CXCL10 production by pDCs via TLR-7/9 and cGAS-STING signaling pathways. As proposed byBased on bulk transcriptomic data, we could confirmed that TGF-β and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234446 | GEO | 2023/12/31

REPOSITORIES: GEO

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TLR-mediated type I IFN induction in pDCs requires the rapamycin-sensitive PI3K-mTOR-p70S6K pathway

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

Chronic Activation of pDCs in Autoimmunity is linked to Dysregulated ER Stress and Metabolic Responses

Project description:Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in multiple autoimmune diseases, such as systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Here, we report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits the production of IFN-α by TLR7- or TLR9-activated pDCs. In SSc patients, pDCs demonstrated reduced expression of UPR marker genes, which inversely correlated with the levels of IFN-I-stimulated genes. CXCL4, a chemokine that is elevated in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation and cAMP signaling, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.

2022-08-15 | GSE211230 | GEO

TLR-mediated type I IFN induction in pDCs requires the rapamycin-sensitive PI3K-mTOR-p70S6K pathway

2008-12-01 | GSE12218 | GEO

Differential Responses of Plasmacytoid Dendritic Cells to Influenza and Distinct Viral Pathogens

Project description:Plasmacytoid dendritic cells (pDCs) are key components of the innate immune response that are capable of synthesizing and rapidly releasing vast amounts of type I interferons (IFNs), particularly IFN-alpha. Here we investigated whether pDCs, often regarded as a mere source of IFN, discriminate between various functionally discrete stimuli and to what extent this reflects differences in pDC responses other than IFN-alpha release. To examine the ability of pDCs to differentially respond to various doses of intact and infectious HIV, hepatitis C virus, and H1N1 influenza virus, whole-genome gene expression analysis, enzyme-linked immunosorbent assays, and flow cytometry were used to investigate pDC responses at the transcriptional, protein, and cellular levels. Our data demonstrate that pDCs respond differentially to various viral stimuli with significant changes in gene expression, including those involved in pDC activation, migration, viral endocytosis, survival, or apoptosis. In some cases, the expression of these genes was induced even at levels comparable to that of IFN-alpha. Interestingly, we also found that depending on the viral entity and the viral titer used for stimulation, induction of IFN-alpha gene expression and the actual release of IFN-alpha are not necessarily temporally coordinated. In addition, our data suggest that high-titer influenza A (H1N1) virus infection can stimulate rapid pDC apoptosis.

2014-07-28 | GSE59837 | GEO

CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and functions

Project description:Plasmacytoid dendritic cells (pDCs) are key regulators of anti-viral immunity. They rapidly secrete IFN-alpha and cross-present viral antigens thereby launching adaptive immunity. Here we show that activated human pDCs inhibit replication of cancer cells, and kill them in a contact dependent fashion. Expression of CD2 distinguishes two pDC subsets with distinct phenotype and function. Both subsets secrete IFN-alpha and express Granzyme B and TRAIL. CD2high pDCs uniquely express lysozyme and can be found in tonsils and in tumors. Both subsets launch recall T cell response. However, CD2high pDCs secrete higher levels of IL12 p40, express higher levels of co-stimulatory molecule CD80 and are more efficient in triggering proliferation of naïve allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions. pDC subsets were isolated from two different donors. They were analyzed in two independent experiments.

2009-05-21 | E-GEOD-15215 | biostudies-arrayexpress

Bruton's Tyrosine Kinase Regulates TLR9 but not TLR7 Signaling in Human pDCs

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

Single-cell analysis reveals stochastic regulation of type I IFN production by plasmacytoid dendritic cells and identifies host-derived environmental cues as amplifier of type I IFN production

Project description:Type I interferon (IFN) is a key driver of immunity to infections and cancer. Plasmacytoid dendritic cells (pDCs) are uniquely equipped to produce large quantities of type I IFN but the mech-anisms that control this process are poorly understood. Here, we developed a droplet-based microfluidic platform and investigated type I IFN production in human pDCs at the single-cell level. We show that type I IFN but not TNF alpha production is limited to a small subpopulation of individually stimulated pDCs and controlled by stochastic gene regulation. Combining single-cell cytokine analysis with single-cell RNA-seq profiling reveals no evidence for a pre-existing subset of type I IFN-producing pDCs. Intriguingly, by modulating the droplet microenvironment, we demonstrate that vigorous pDC population responses are driven by a type I IFN amplification loop. Our study highlights the significance of stochastic gene regulation and suggests strategies to dissect the characteristics of immune responses at the single-cell level.

2018-08-22 | GSE114161 | GEO

Proteomic and single-cell transcriptomic dissection of human plasmacytoid dendritic cell response to influenza virus

Project description:Plasmacytoid dendritic cells [pDCs] represent a rare innate immune subset uniquely endowed with the capacity to produce substantial amounts of type-I interferons [IFN-I]. This function of pDCs is critical for effective antiviral defenses and has been implicated in autoimmunity. While IFN-I and select cytokines have been recognized as pDC secreted products, a comprehensive agnostic profiling of the pDC secretome in response to a physiologic stimulus has not been reported. We applied LC-MS/MS to catalogue the repertoire of proteins secreted by pDCs in response to challenge with live influenza H1N1. Additionally, using single-cell RNA-seq [scRNA-seq], we perform multidimensional analyses of pDC transcriptional diversification following stimulation. Our data reveal an abundance of protein species released by pDCs in addition to IFN-I, and evidence highly specialized roles within the pDC population ranging from dedicated cytokine super-producers to cells with APC-like functions. Moreover, dynamic expression of transcription factors and surface markers characterize activated pDC fates.

2021-11-12 | MSV000088375 | MassIVE

The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells [RNA-seq]

Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.

2020-05-23 | GSE148902 | GEO

The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells [microarray]

2020-05-23 | GSE149415 | GEO

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