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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE12218 | GEO | 2008/12/01

SECONDARY ACCESSION(S): PRJNA113673

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

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

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

2015-10-24 | GSE41825 | GEO

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

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

Project description: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.

2023-12-31 | GSE234446 | GEO

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

Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells

Project description:Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, the human cytomegalovirus (CMV). Human pDCs responded poorly to free CMV but strongly to live CMV-infected fibroblasts, in a process that involved integrin-mediated adhesion, transfer of viral DNA to pDCs and its recognition through TLR9. Compared to transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of type I (IFN-I) and type III (IFN-III) interferons, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells that are critical for CMV control. Finally, patients with CMV viremia harbored phenotypically activated pDCs and increased levels of IFN-I and IFN-III in circulation. Thus, recognition of live infected cells is a common mechanism of virus detection by pDCs that elicits a unique antiviral response program.

2021-03-01 | GSE163707 | GEO

Free cholesterol primes the IFN-I response

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 |

Type-I interferon inducible genes 26 weeks after mCMV infection in Siglec-H wt and Siglec-H ko mice and their non infected controls

Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.

2016-03-16 | GSE79248 | 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

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