EBI2 Is a Negative Regulator of Type I Interferons in Plasmacytoid and Myeloid Dendritic Cells
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{"title"=>"EBI2 is a negative regulator of type I interferons in plasmacytoid and myeloid dendritic cells", "type"=>"journal", "authors"=>[{"first_name"=>"Eugene Y.", "last_name"=>"Chiang", "scopus_author_id"=>"18338882800"}, {"first_name"=>"Robert J.", "last_name"=>"Johnston", "scopus_author_id"=>"36007280200"}, {"first_name"=>"Jane L.", "last_name"=>"Grogan", "scopus_author_id"=>"7005630417"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "pui"=>"372294868", "pmid"=>"24386204", "doi"=>"10.1371/journal.pone.0083457", "sgr"=>"84893442028", "scopus"=>"2-s2.0-84893442028"}, "id"=>"a147629d-5ac1-3c84-8cd5-8770b55ba169", "abstract"=>"Epstein-Barr virus induced receptor 2 (EBI2), a Gαi- coupled G protein-coupled receptor, is a chemotactic receptor for B, T and dendritic cells (DC). Genetic studies have also implicated EBI2 as a regulator of an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) associated with autoimmune diseases, although the corollary in primary type I IFN-producing cells has not been reported. Here we demonstrate that EBI2 negatively regulates type I IFN responses in plasmacytoid DC (pDCs) and CD11b+ myeloid cells. Activation of EBI2-/- pDCs and CD11b+ cells with various TLR ligands induced elevated type I IFN production compared to wild-type cells. Moreover, in vivo challenge with endosomal TLR agonists or infection with lymphocytic choriomeningitis virus elicited more type I IFNs and proinflammatory cytokines in EBI2-/- mice compared to normal mice. Elevated systemic cytokines occurred despite impaired ability of EBI2-deficient pDCs and CD11b+ cells to migrate from the blood to the spleen and peritoneal cavity under homeostatic conditions. As reported for other immune cells, pDC migration was dependent on the ligand for EBI2, 7α,25-dihydroxycholesterol. Consistent with a cell intrinsic role for EBI2, type I IFN-producing cells from EBI2-deficient mice expressed higher levels of IRF7 and IDIN genes. Together these data suggest a negative regulatory role for EBI2 in balancing TLR-mediated responses to foreign and to self nucleic acids that may precipitate autoimmunity. © 2013 Chiang et al.", "link"=>"http://www.mendeley.com/research/ebi2-negative-regulator-type-i-interferons-plasmacytoid-myeloid-dendritic-cells", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>8, "Student > Ph. D. Student"=>9, "Other"=>4, "Student > Master"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>8, "Student > Ph. D. Student"=>9, "Other"=>4, "Student > Master"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>12, "Medicine and Dentistry"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1328960"], "description"=>"<p>IDIN gene expression was determined by real-time RT-PCR. Expression in unstimulated or TLR9 agonist CpG-A ODN2216, TLR7 agonist ssPolyU, TLR3 agonist poly(I:C) or TLR4 agonist LPS stimulated pDCs (<b>A</b>) or CD11b<sup>+</sup> monocytes/macrophages (<b>B</b>) from WT (white bars) or EBI2 KO (shaded bars) mice. Gene expression is presented relative to <i>RPL19</i> expression. Data are shown as mean ± s.d. from a single experiment with duplicate measurements. The experiment was repeated with similar results.</p>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling", "irf7", "idin", "genes", "tlr-stimulated", "ebi2-deficient", "pdcs"], "article_id"=>886893, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083457.g007", "stats"=>{"downloads"=>0, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_IRF7_and_IDIN_genes_in_TLR_stimulated_EBI2_deficient_pDCs_and_monocytes_macrophages_/886893", "title"=>"Expression of IRF7 and IDIN genes in TLR-stimulated EBI2-deficient pDCs and monocytes/macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-26 04:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1328959"], "description"=>"<p>pDCs or CD11b<sup>+</sup> monocyte/macrophages from WT or <i>Ebi2</i><sup>−/−</sup> littermate mice were preincubated with 100 ng/ml PTX, and then stimulated with TLR7 agonist ssPolyU (<b>A</b>), TLR9 agonist CpG-A ODN2216 (<b>B</b>) or TLR3 agonist poly(I:C) (<b>C</b>). IFN-α secretion in culture supernatants after 40 hr stimulation were measured by ELISA. Bars represent mean values of 3 independently performed experiments (white denotes WT, shaded denotes KO); circles represent individual experiments. <i>P</i>-values are denoted when considered statistically significant (<i>p</i><0.05); n.s. denotes not statistically significant. IFN-α was not detectable in the absence of stimulation.</p>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling", "ifn", "enhanced", "pertussis", "toxin"], "article_id"=>886892, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083457.g006", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Type_I_IFN_production_is_enhanced_by_pertussis_toxin_treatment_/886892", "title"=>"Type I IFN production is enhanced by pertussis toxin treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-26 04:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1328952"], "description"=>"<p>Flow cytometric analysis was used to enumerate pDCs, myeloid DCs and B cells in WT (white bars) or <i>Ebi2</i><sup>−/−</sup> (shaded bars) mice (n = 7 per group for spleens; n = 5 per group for peritoneal lavage fluid). Bars represent mean values; white denotes WT, shaded denotes KO; circles represent individual animals. <i>P</i>-values are denoted when considered statistically significant (<i>p</i><0.05).</p>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling", "spleen", "peritoneal", "lavage", "wt"], "article_id"=>886889, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083457.g004", "stats"=>{"downloads"=>2, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immune_cell_distribution_in_Ebi2__mice_Immune_cell_distribution_in_spleen_A_or_peritoneal_lavage_fluid_B_of_na_ve_WT_and_Ebi2_8722_8722_mice_/886889", "title"=>"Immune cell distribution in <i>Ebi2</i><sup>−<b>/</b>−</sup> mice. Immune cell distribution in spleen (A) or peritoneal lavage fluid (B) of naïve WT and <i>Ebi2</i><sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-26 04:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1328944"], "description"=>"<p><b>A</b>, <b>B</b>. EBI2 ligand 7α,25-OHC induces migration of pDCs. <i>In vitro</i> migration studies of unstimulated (<b>A</b>) or TLR9 agonist CpG-A ODN2216 activated (<b>B</b>) pDCs from EBI2 WT (white bars) or KO (shaded bars) mice towards 7α,25-OHC (indicated concentrations) or 25-OHC (10<sup>−6</sup> M). Starting cells and migrating cells were analyzed by specific staining for pDCs and flow cytometry. Data shown are representative of two separate experiments. <b>C</b>. Stimulation of activated pDCs with 7α,25-OHC does not affect IFN-α production. pDCs activated with CpG-A were stimulated for 40 hr with 25-OHC (10<sup>−6</sup> M) or 7α,25-OHC. IFN-α concentrations in cell supernatants were determined by ELISA. Data are shown as mean ± s.d. from a single experiment with duplicate measurements. The experiment was repeated with similar results.</p>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling", "ifn-producing", "cells", "functions", "chemotactic"], "article_id"=>886887, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083457.g003", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EBI2_expressed_by_type_I_IFN_producing_cells_functions_as_a_chemotactic_receptor_/886887", "title"=>"EBI2 expressed by type I IFN-producing cells functions as a chemotactic receptor.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-26 04:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1328943"], "description"=>"<p><b>A</b>. Quantitative PCR analysis of <i>Ebi2</i> transcript abundance was performed in purified T cells, B cells and indicated myeloid cell populations. <b>B</b>. Expression of <i>Ebi2</i> in TLR-stimulated pDCs and CD11b<sup>+</sup> myeloid cells. <i>Ebi2</i> expression in purified pDCs and CD11b<sup>+</sup> myeloid cells that were stimulated for various time points over a 40 hr period with indicated TLR agonist. <i>Ebi2</i> expression in each cell type was normalized to <i>RPL19</i> expression, and data are shown as <i>Ebi2</i> expression relative to unstimulated cells at the corresponding time point. Data are shown as mean ± s.d. of two independent experiments.</p>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling"], "article_id"=>886886, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083457.g002", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immune_cell_expression_of_EBI2_/886886", "title"=>"Immune cell expression of EBI2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-26 04:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1328963", "https://ndownloader.figshare.com/files/1328964", "https://ndownloader.figshare.com/files/1328965", "https://ndownloader.figshare.com/files/1328966"], "description"=>"<div><p>Epstein-Barr virus induced receptor 2 (EBI2), a Gα<sub>i</sub>-coupled G protein-coupled receptor, is a chemotactic receptor for B, T and dendritic cells (DC). Genetic studies have also implicated EBI2 as a regulator of an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) associated with autoimmune diseases, although the corollary in primary type I IFN-producing cells has not been reported. Here we demonstrate that EBI2 negatively regulates type I IFN responses in plasmacytoid DC (pDCs) and CD11b<sup>+</sup> myeloid cells. Activation of EBI2<sup>−/−</sup> pDCs and CD11b<sup>+</sup> cells with various TLR ligands induced elevated type I IFN production compared to wild-type cells. Moreover, <i>in vivo</i> challenge with endosomal TLR agonists or infection with lymphocytic choriomeningitis virus elicited more type I IFNs and proinflammatory cytokines in EBI2<sup>−/−</sup> mice compared to normal mice. Elevated systemic cytokines occurred despite impaired ability of EBI2-deficient pDCs and CD11b<sup>+</sup> cells to migrate from the blood to the spleen and peritoneal cavity under homeostatic conditions. As reported for other immune cells, pDC migration was dependent on the ligand for EBI2, 7α,25-dihydroxycholesterol. Consistent with a cell intrinsic role for EBI2, type I IFN-producing cells from EBI2-deficient mice expressed higher levels of IRF7 and IDIN genes. Together these data suggest a negative regulatory role for EBI2 in balancing TLR-mediated responses to foreign and to self nucleic acids that may precipitate autoimmunity.</p></div>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling", "interferons", "plasmacytoid", "myeloid", "dendritic"], "article_id"=>886896, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0083457.s001", "https://dx.doi.org/10.1371/journal.pone.0083457.s002", "https://dx.doi.org/10.1371/journal.pone.0083457.s003", "https://dx.doi.org/10.1371/journal.pone.0083457.s004"], "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EBI2_Is_a_Negative_Regulator_of_Type_I_Interferons_in_Plasmacytoid_and_Myeloid_Dendritic_Cells_/886896", "title"=>"EBI2 Is a Negative Regulator of Type I Interferons in Plasmacytoid and Myeloid Dendritic Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-12-26 04:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1328957"], "description"=>"<p>pDCs or CD11b<sup>+</sup> monocyte/macrophages from <i>Ebi2</i><sup>−/−</sup> or WT littermate mice were stimulated with TLR7 agonist ssPolyU (<b>A</b>), TLR9 agonist CpG-A ODN2216 (<b>B</b>) or TLR3 agonist poly(I:C) (<b>C</b>). IFN-α secretion in culture supernatants after 40 hr stimulation were measured by ELISA. Cells were purified from pools of 2 spleens each. 8 mice from each group were used, resulting in 4 pools. Bars represent mean values (white denotes WT, shaded denotes KO); circles represent each pool. <i>P</i>-values are denoted when considered statistically significant (<i>p</i><0.05). IFN-α was not detectable in the absence of stimulation. <b>D</b>. Rescue of EBI2 expression in EBI2-deficient pDCs reduces type I IFN response to normal levels. EBI2 KO (shaded bars) or WT (white bars) pDCs were transiently transfected with EBI2 or control vector, counted and plated, then stimulated with TLR9 agonist CpG-A ODN2216. IFN-α concentrations in supernatants were measured by ELISA 40 hr after stimulation. Data are shown as mean ± s.d. of duplicate measurements. The experiment was repeated twice with similar results in each. <b>E</b>. Quantitative PCR analysis of <i>Ebi2</i> transcript abundance was performed with <i>Ebi2</i> expression presented relative to <i>RPL19</i> expression. Data are shown as mean ± s.d. of triplicate measurements; < l.o.d. denotes below limit of detection.</p>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling", "mice", "activated", "tlr7", "tlr9"], "article_id"=>886890, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083457.g005", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_pDCs_from_Ebi2_8722_8722_mice_produce_more_IFN_945_when_activated_with_TLR7_or_TLR9_agonists_/886890", "title"=>"pDCs from <i>Ebi2</i><sup>−/−</sup> mice produce more IFN-α when activated with TLR7 or TLR9 agonists.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-26 04:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1328942"], "description"=>"<p><b>A, B.</b> Type I IFN production in mice challenged i.p. with TLR7 agonist Imiquimod (<b>A</b>) or TLR3 agonist poly(I:C) (<b>B</b>). IFN-α and IFN-β concentrations in peritoneal lavage fluid 4 hr following challenge were determined by ELISA. Bars represent mean values (white denotes WT, shaded denotes KO; n = 5 per group); circles represent individual animals. <b>C</b>. LCMV Cl13 infection in <i>Ebi2</i><sup>−/−</sup> mice. <i>Ebi2</i><sup>−/−</sup> (shaded bars) or WT littermate (white bars) mice were infected with 2×10<sup>6</sup> PFU LCMV Cl13 i.v. On day 3, serum type I IFN concentrations were determined by ELISA. Bars denote mean values; circles represent individual animals (n = 5 per group). <i>P</i>-values are denoted when considered statistically significant (<i>p</i><0.05). IFN-α concentrations in naïve mice were below assay limit of detection.</p>", "links"=>[], "tags"=>["immunology", "Immune system", "cytokines", "immunity", "Immune activation", "Innate immunity", "autoimmunity", "Genetics of the immune system", "Immune cells", "Immune response", "Model organisms", "Animal models", "mouse", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "G-protein signaling", "mice", "stronger", "ifn", "responses", "tlr", "agonists", "lcmv"], "article_id"=>886885, "categories"=>["Biological Sciences"], "users"=>["Eugene Y. Chiang", "Robert J. Johnston", "Jane L. Grogan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0083457.g001", "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ebi2__mice_have_stronger_pDC_medi_ted_type_I_IFN_responses_to_in_vivo_challenge_with_TLR_agonists_or_LCMV_Cl13_/886885", "title"=>"<i>Ebi2</i><sup>−<b>/</b>−</sup> mice have stronger pDC-mediαted type I IFN responses to <i>in vivo</i> challenge with TLR agonists or LCMV Cl13.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-26 04:11:14"}

PMC Usage Stats | Further Information

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Relative Metric

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