The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake

Immunity ◽  
2021 ◽  
Author(s):  
Álvaro de Mingo Pulido ◽  
Kay Hänggi ◽  
Daiana P. Celias ◽  
Alycia Gardner ◽  
Jie Li ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Extracellular Dna ◽  
Dna Uptake ◽  
Inhibitory Receptor ◽  
Sting Pathway

Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.

2020 ◽  
Author(s):  
GUANGHOU FU ◽  
XIAOYI CHEN ◽  
ZHIJIE XU ◽  
JUNJIE SU ◽  
JUNJIE TIAN ◽  
...  
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Tumor Model ◽  
Cancer Microenvironment ◽  
Cancer Proliferation ◽  
Advanced Bladder Cancer ◽  
Sting Pathway

Abstract Background Cisplatin is a commonly used adjuvant chemotherapy for advanced bladder cancer, but its immune related mechanism is still unclear. Exploration the immune effects of cisplatin in bladder cancer would complement the comprehensive mechanism of cisplatin and provide the basis for combination therapy of cisplatin and immunotherapy in bladder cancer. Methods We confirmed the immune effects of cisplatin on T24 and TCCSUP bladder cancer cell lines in vitro and exploration the important function of these immune effects in bladder cancer microenvironment in mice tumor model. Results We found cisplatin induced immune response in bladder cancer by RNA sequencing, and validated cGAS-STING signal was deeply involved in this response. Cisplatin induced cGAS-STING signal inhibited the proliferation of bladder cancer and increased the infiltration percentages of CD8 + T cells and dendritic cells in transplantation mice tumor model. Accumulation of dsDNA and the release of chromatin bound cGAS are important to activate downstream STING. Conclusion Our findings indicated a cisplatin related immune effects in bladder cancer, cisplatin combined with immunotherapy might have a synergistic effect for bladder cancer therapy.

scholarly journals The Immune Inhibitory Receptor LAIR-1 Is Highly Expressed by Plasmacytoid Dendritic Cells and Acts Complementary with NKp44 to Control IFNα Production

PLoS ONE ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. e15080 ◽  
Author(s):  
Irene Bonaccorsi ◽  
Claudia Cantoni ◽  
Paolo Carrega ◽  
Daniela Oliveri ◽  
Gabrielle Lui ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Inhibitory Receptor

scholarly journals Correction: miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 305
Author(s):  
Abid Ullah Shah ◽  
Yanan Cao ◽  
Naila Siddique ◽  
Jian Lin ◽  
Qian Yang
Keyword(s):  
Dendritic Cells ◽  
Sting Pathway

The authors wish to make the following corrections to this paper [...]

scholarly journals A Novel Inhibitory Receptor (ILT3) Expressed on Monocytes, Macrophages, and Dendritic Cells Involved in Antigen Processing

1997 ◽  
Vol 185 (10) ◽  
pp. 1743-1751 ◽  
Author(s):  
Marina Cella ◽  
Christian Döhring ◽  
Jacqueline Samaridis ◽  
Mark Dessing ◽  
Manfred Brockhaus ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antigen Processing ◽  
Tyrosine Phosphatase ◽  
Immunoglobulin Superfamily ◽  
Cross Linking ◽  
Inhibitory Receptor ◽  
Cell Surface Molecule ◽  
Antigen Uptake ◽  
Inhibitory Function ◽  
Antigen Presenting

Immunoglobulin-like transcript (ILT) 3 is a novel cell surface molecule of the immunoglobulin superfamily, which is selectively expressed by myeloid antigen presenting cells (APCs) such as monocytes, macrophages, and dendritic cells. The cytoplasmic region of ILT3 contains putative immunoreceptor tyrosine-based inhibitory motifs that suggest an inhibitory function of ILT3. Indeed, co-ligation of ILT3 to stimulatory receptors expressed by APCs results in a dramatic blunting of the increased [Ca2+]i and tyrosine phosphorylation triggered by these receptors. Signal extinction involves SH2-containing protein tyrosine phosphatase 1, which is recruited by ILT3 upon cross-linking. ILT3 can also function in antigen capture and presentation. It is efficiently internalized upon cross-linking, and delivers its ligand to an intracellular compartment where it is processed and presented to T cells. Thus, ILT3 is a novel inhibitory receptor that can negatively regulate activation of APCs and can be used by APCs for antigen uptake.

Inhibition of mTOR suppresses IFNα production and the STING pathway in monocytes from systemic lupus erythematosus patients

Rheumatology ◽  
2020 ◽  
Vol 59 (10) ◽  
pp. 2992-3002 ◽  
Author(s):  
Goh Murayama ◽  
Asako Chiba ◽  
Taiga Kuga ◽  
Ayako Makiyama ◽  
Ken Yamaji ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Intracellular Cytokine Staining ◽  
Plasmacytoid Dendritic Cells ◽  
Mtor Pathway ◽  
Pathway Activation ◽  
Sting Pathway

Abstract Objective Increased IFNα is important in the pathogenesis of SLE. Plasmacytoid dendritic cells are considered the main producer of IFNα upon Toll-like receptor pathway activation. However, which cells produce IFNα following stimulation with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) in SLE remains unknown. We investigated the IFNα producing capacity of myeloid cells under cGAS-STING pathway stimulation. Methods IFNα levels in peripheral blood mononuclear cells from SLE patients and healthy controls stimulated with 2′3′c-GAMP, a stimulator of cGAS-STING, were measured by intracellular cytokine staining and flow cytometry. STING expression and its co-localization with TBK1 were examined by flow cytometry or confocal microscopy. The effects of in vitro exposure to IFNα on IFNα production and STING expression, and in vitro rapamycin treatment on IFNα production and STING, pTBK1 and IRF3 expression were examined. Results IFNα was produced by monocytes, conventional dendritic cells and plasmacytoid dendritic cells upon cGAS-STING pathway activation. The frequency of IFNα-producing monocytes positively correlated with SLE disease activity. STING expression and its co-localization with TBK1 were increased in lupus monocytes. Prior exposure to IFNα enhanced the IFNα-producing capacity of monocytes. Inhibition of the mechanistic target of the rapamycin (mTOR) pathway suppressed IFNα production from monocytes and downregulated enhanced STING expression and its downstream molecules. Conclusion Enhanced IFNα from lupus monocytes induced by augmented STING pathway activation is associated with SLE pathogenesis. Suppression of the mTOR pathway downregulated the enhanced STING expression and the subsequent IFNα production by monocytes.

scholarly journals miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 197 ◽  
Author(s):  
Abid Ullah Shah ◽  
Yanan Cao ◽  
Naila Siddique ◽  
Jian Lin ◽  
Qian Yang
Keyword(s):  
Dendritic Cells ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Mouse Bone Marrow ◽  
Cytokine Detection ◽  
Sting Pathway ◽  
Factor Α ◽  
Antigen Presenting ◽  
And Control

The Cytosine–phosphate–guanosine (CpG) motif, which is specifically recognized intracellularly by dendritic cells (DCs), plays a crucial role in regulating the innate immune response. MicroRNAs (miRNAs) can strongly influence the antigen-presenting ability of DCs. In this study, we examine the action of miRNAs on CpG-stimulated and control DCs, as well as their effect on cyclic guanosine monophosphate-adenosine monophosphate (GMP–AMP) synthase (cGAS) and the stimulator of interferon genes (STING) signal pathway. Firstly, we selected miRNAs (miR-29a and miR-378b) based on expression in CpG-stimulated mouse bone marrow-derived dendritic cells (BMDCs). Secondly, we investigated the functions of miR-29a and miR-378b on CpG-stimulated and unstimulated BMDCs. The results showed that miR-29a and miR-378b increased expression of both the immunoregulatory DC surface markers (CD86 and CD40) and the immunosuppressive molecule CD273 by DCs. Thirdly, cytokine detection revealed that both miR-29a and miR-378b enhanced interferon-β (IFN-β) expression while suppressing tumor necrosis factor-α (TNF-α) production. Finally, our results suggest that miR-378b can bind TANK-binding kinase binding protein 1 (TBKBP1) to activate the cGAS/STING signaling pathway. By contrast, miR-29a targeted interferon regulatory factor 7 (IRF7) and promoted the expression of STING. Together, our results provide insight into the molecular mechanism of miRNA induction by CpG to regulate DC function.

scholarly journals Quantitative Determination of Free-DNA Uptake in River Bacteria at the Single-Cell Level by In Situ Rolling-Circle Amplification

2006 ◽  
Vol 72 (9) ◽  
pp. 6248-6256 ◽  
Author(s):  
Fumito Maruyama ◽  
Katsuji Tani ◽  
Takehiko Kenzaka ◽  
Nobuyasu Yamaguchi ◽  
Masao Nasu
Keyword(s):  
Single Cell ◽  
Gene Amplification ◽  
Rolling Circle Amplification ◽  
Extracellular Dna ◽  
Single Cell Level ◽  
Dna Uptake ◽  
Cell Level ◽  
Indigenous Bacteria ◽  
Rolling Circle

ABSTRACT Detection of plasmid DNA uptake in river bacteria at the single-cell level was carried out by rolling-circle amplification (RCA). Uptake of a plasmid containing the green fluorescent protein gene (gfp) by indigenous bacteria from two rivers in Osaka, Japan, was monitored for 506 h using this in situ gene amplification technique with optimized cell permeabilization conditions. Plasmid uptake determined by in situ RCA was compared to direct counts of cells expressing gfp under fluorescence microscopy to examine differences in detection sensitivities between the two methods. Detection of DNA uptake as monitored by in situ RCA was 20 times higher at maximum than that by direct counting of gfp-expressing cells. In situ RCA could detect bacteria taking up the plasmid in several samples in which no gfp-expressing cells were apparent, indicating that in situ gene amplification techniques can be used to determine accurate rates of extracellular DNA uptake by indigenous bacteria in aquatic environments.

Spatiotemporal regulation of intracellular trafficking of Toll-like receptor 9 by an inhibitory receptor, Ly49Q

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1518-1527 ◽  
Author(s):  
Mariko Yoshizaki ◽  
Aya Tazawa ◽  
Eiji Kasumi ◽  
Shigemi Sasawatari ◽  
Kenji Itoh ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Natural Killer ◽  
Membrane Trafficking ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Inhibitory Receptor ◽  
Toll Like Receptor ◽  
Spatiotemporal Regulation ◽  
Cpg Oligodeoxynucleotide ◽  
Tlr9 Signaling

Abstract Toll-like receptor (TLR) 9 recognizes unmethylated microorganismal cytosine guanine dinucleotide (CpG) DNA and elicits innate immune responses. However, the regulatory mechanisms of the TLR signaling remain elusive. We recently reported that Ly49Q, an immunoreceptor tyrosine-based inhibitory motif–bearing inhibitory receptor belonging to the natural killer receptor family, is crucial for TLR9-mediated type I interferon production by plasmacytoid dendritic cells. Ly49Q is expressed in plasmacytoid dendritic cells, macrophages, and neutrophils, but not natural killer cells. In this study, we showed that Ly49Q regulates TLR9 signaling by affecting endosome/lysosome behavior. Ly49Q colocalized with CpG in endosome/lysosome compartments. Cells lacking Ly49Q showed a disturbed redistribution of TLR9 and CpG. In particular, CpG-induced tubular endolysosomal extension was impaired in the absence of Ly49Q. Consistent with these findings, cells lacking Ly49Q showed impaired cytokine production in response to CpG-oligodeoxynucleotide. Our data highlight a novel mechanism by which TLR9 signaling is controlled through the spatiotemporal regulation of membrane trafficking by the immunoreceptor tyrosine-based inhibitory motif–bearing receptor Ly49Q.

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