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Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation

ABSTRACT: Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the down-stream effectors of type I IFN signaling that amplify autoimmune responses. Here we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation conventional type 1 and type 2 DCs (cDC1 and cDC2 respectively) uniformly upregulate CXCL10. By contrast, the proportion of chemokine positive pDCs was significantly less, and stable CXCL10+ and CXCL10 - populations could be distinguished. CXCL9 expression was induced in all cDC1s, in half of the cDC2 but not by pDCs. In all DC subsets, type I IFNs were the main inducer of CXCR3 chemokines, as IFNAR receptor blocking or deficiency completely abrogated reporter expression. Chemoki ne producing potential was not concordant with the previously identified markers of pDC heterogeneity. Finally, we show that CXCL10+ and CXCL10 - populations are transcriptionally distinct, expressing unique transcriptional regulators, IFN signaling molecules, chemokines, cytokines and cell surface markers. This work highlights CXCL10 as a downstream effector of type I IFN signaling and suggests a division of labor in pDCs subtypes that likely impacts their function as effectors of viral responses and as drivers of inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE113770 | GEO | 2018/06/24

REPOSITORIES: GEO

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Plasmacytoid dendritic cell heterogeneity is defined by CXCL10 expression following TLR7 stimulation

Project description:We have used chemokine reporter mice to investigate down-stream effectors of type I IFN signaling, the chemokines of the CXCR3 family. We show that pDCs and conventional DCs display unique chemokine expression profiles that are dependent on IFNAR1 signaling. We go onto show that, following stimulation, pDCs form two stable and transcriptionally distinct populations based on their expression of CXCL10.

2019-12-26 | GSE110975 | GEO

Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation

Project description:Chemokines are chemotactic cytokines that control the migratory patterns and positioning of immune cells. Many chemokines have been associated with systemic autoimmune diseases that have chronic IFN signature. We now describe that a series of chemokines, including CXCL4, CXCL10, CXCL12 and CCL5, can superinduce type I IFN (IFN-I) by TLR9-activated plasmacytoid DCs (pDCs), independently of their respective known chemokine receptors. Mechanistically, we show that chemokines such as CXCL4 mediate transcriptional and epigenetic changes in pDCs, mostly targeted to the IFN-I pathways. We also describe that chemokines physically interact with DNA to form nanoparticles which promote clathrin-mediated cellular uptake and delivery of DNA in the early endosomes of pDCs. Using two mouse models of skin inflammation, we observed the presence of CXCL4 associated with DNA in vivo. These data thus reveal a non-canonical role for chemokines to modulate TLR signaling, and extend our understanding on the mechanism associated with the chronic expression of IFN-I by pDCs in autoimmune diseases.

2022-05-24 | GSE202333 | GEO

Microarray analysis of minor salivary glands from patients with primary Sjögren’s syndrome (SS) or non-SS

Project description:Objective. A variety of chemokines contribute the pathogenesis of Sjögren’s syndrome (SS). However, the comprehensive analysis as for clinically potent ckemokines in SS has not been performed. In this study, focusing on CXC chemokines, we investigated the precise molecular mechanism and the clinical significance through chemokine and its receptor in the autoimmune lesions of primary SS. Methods. Gene expression profiles in the lip salivary glands (LSGs) from pSS patients and controls were analyzed using DNA microarray. Expression of chemokines and their receptor of biopsy samples of pSS pathients and controls were detected by immunofluorescence analysis. In addition, in vitro experiments using human salivary gland ductal and acinar cell lines were performed to analyze the expression of chemokines and signaling pathwaycytokines by qRT-PCR, ELISA, and Western blot analysis. Results. Gene expression profiles and immunohistochemical analysis revealed that IFN-γ-induced CXCL9 and CXCL10 were significantly increased in LSGs of pSS patients. In vitro experiments revealed that the protein expression of CXCL10 in ductal and acinar cells was differentially regulated by IFN-γ or TNF-α via NF-κB or JAK/STAT pathway. Moreover, CXCR3 expression was detected mainly in CD68+ macrophages, CD123+ plasmacytoid dendritic cells (pDCs), and in a few CD3+ T cells. Finally, Spearman's rank analysis revealed a negative correlation between the existence of CXCR3+ cells and pathological grading in LSG tissues of pSS patients (r: -0.019, p<0.01). Conclusion. These results suggest that CXCL10/CXCR3 axis plays in a key role in autoimmune response by interaction between immune cells and target cells in the pathogenesis of pSS.

2016-08-31 | GSE80805 | GEO

IFN? expression is restricted to a subpopulation of splenic pDCs exhibiting a specific immune modulatory transcriptome signature

Project description:Type I IFNs are critical in initiating protective antiviral immune responses and plasmacytoid DCs (pDCs) represent a major source of these cytokines. Here we show that only few pDCs are capable to produce IFN? after virus infection or CpG stimulation. Utilizing IFN?/YFP reporter mice, we identify these IFN?-producing cells in the spleen as a CCR9+CD9- pDC subset exclusively localized within the T/B cell zones. IFN?-producing pDCs exhibit a distinct transcriptome profile with higher expression of genes encoding cytokines and chemokines, facilitating T cell recruitment and activation. These distinctive characteristics of IFN?-producing pDCs are independent of the type I IFN receptor mediated feedback loop. Furthermore, IFN?-producing pDCs exhibit enhanced CCR7-dependent migratory properties in vitro and in a peritoneal inflammation model they effectively recruit T cells in vivo. We define “professional type I IFN-producing cells” as a distinct subset of pDCs specialized in coordinating cellular immune responses. IFN? associated gene expression in ex vivo sorted IFN?/YFPpos vs. IFN?/YFPneg splenic pDCs was measured at 6 hr after i.v. injection of CpG 1668 complexed to DOTAP. Two independent experiments were performed using pooled samples of at least 12 mice per experiment.

2015-05-27 | E-GEOD-68788 | biostudies-arrayexpress

RNAseq of CD8 T-cells stimulated with CXCR3 chemokines

Project description:G protein-coupled receptors (GPCRs) interact with many transducers like G proteins and β-arrestins. Some GPCR agonists act as “biased agonists” which preferentially activate specific signaling transducers over others, leading to unique signaling profiles. The chemokine system, a subfamily of GPCRs that plays a critical role in inflammatory diseases, serves as an endogenous example of biased agonism where over 50 different chemokines ligands and 20 receptors interact promiscuously. In this study, we sought to determine the three different chemokines of the chemkoine receptor CXCR3 generate different transcriptional responses in primary CD8+ T cells. Using RNAseq on CD8+ T cells stimulated with either vehicle control, CXCL9, CXCL10, or CXCL11, the endogenous chemokines of CXCR3, we found that the CXCR3 chemokines promoted unique transcriptional responses that are predicted to differentially regulate inflammatory pathways. We observed significant changes in global transcriptional activation, detecting approximately 48000 transcripts, 887 of which varied by chemokine treatment. There was a high degree of replicability between biological replicates. The overwhelming majority of differentially expressed genes (DEGs) increased in transcript level following chemokine treatment. Compared to vehicle control, CXCL11 demonstrated the largest number of DEGs. Importantly, CXCL11 and CXCL10 demonstrate unique transcriptional profiles where the majority of DEGs were only found following treatment with each specific chemokine, rather than being shared across chemokines. These data contrast with that observed at CXCL9 – although it promoted a significant amount of transcriptional regulation, approximately 66% of CXCL9-induced DEGs were shared with CXCL11 and/or CXCL10.

2022-07-23 | GSE192679 | GEO

Immune Response of Immature Dendritic Cells after Infection with Human Cytomegalovirus Strain TB40E

Project description:Microarray analysis and quantitative real-time PCR revealed that TB40E infection of DCs led to changes of the gene expression pattern. A variety of pro-inflammatory cytokines and chemokines (CXCL10, CXCL11, CCL5), TLR3 and genes whose products function downstream of the TLR3 signalling pathway (e.g. IFN-alpha, IFN-beta) were significantly upregulated. Three mock transfected DC vs. three TB40 transfected DCs

2009-08-01 | E-GEOD-14816 | biostudies-arrayexpress

Pro-inflammatory Beta Cell Small Extracellular Vesicles Induce Beta Cell Failure Through Activation of the CXCL10/CXCR3 Axis in Diabetes

Project description:Coordinated communication among pancreatic islet cells is necessary for the maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β-cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β-cell stress. We report that pro-inflammatory β-cell small EVs (cytoEV) induce β-cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8+ T-cells and macrophages. Proteomic analysis of cytoEV revealed an enrichment of the chemokine, CXCL10, with surface topological analysis depicting CXCL10 as membrane-bound on cytoEV to facilitate direct binding to CXCR3 receptors on the surface of β-cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β-cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. Collectively, this work implicates the significant role of pro-inflammatory β-cell derived small EVs in modulating β-cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.

2021-08-25 | PXD026998 | Pride

Cxcr3 expressing leukocytes are necessary for neurofibroma formation in mice

Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the Cxcl10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.

2018-11-28 | GSE122999 | GEO

Cxcr3 expressing leukocytes are necessary for neurofibroma formation in mice

Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor, Cxcr3, prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.

2019-02-24 | GSE122730 | GEO

IFNβ expression is restricted to a subpopulation of splenic pDCs exhibiting a specific immune modulatory transcriptome signature

Project description:Type I IFNs are critical in initiating protective antiviral immune responses and plasmacytoid DCs (pDCs) represent a major source of these cytokines. Here we show that only few pDCs are capable to produce IFNβ after virus infection or CpG stimulation. Utilizing IFNβ/YFP reporter mice, we identify these IFNβ-producing cells in the spleen as a CCR9+CD9- pDC subset exclusively localized within the T/B cell zones. IFNβ-producing pDCs exhibit a distinct transcriptome profile with higher expression of genes encoding cytokines and chemokines, facilitating T cell recruitment and activation. These distinctive characteristics of IFNβ-producing pDCs are independent of the type I IFN receptor mediated feedback loop. Furthermore, IFNβ-producing pDCs exhibit enhanced CCR7-dependent migratory properties in vitro and in a peritoneal inflammation model they effectively recruit T cells in vivo. We define “professional type I IFN-producing cells” as a distinct subset of pDCs specialized in coordinating cellular immune responses.

2015-05-27 | GSE68788 | GEO

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