IRF1

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Philippe Gros - One of the best experts on this subject based on the ideXlab platform.

  • role of irf8 in immune cells functions protection against infections and susceptibility to inflammatory diseases
    Human Genetics, 2020
    Co-Authors: Sandra Salem, David Salem, Philippe Gros
    Abstract:

    The transcription factor IRF8 (ICSBP) is required for the development and maturation of myeloid cells (dendritic cells, monocytes, macrophages), and for expression of intrinsic anti-microbial function such as antigen capture, processing and presentation to lymphoid cells, and for activation of these cells in response to cytokines and pro-inflammatory stimuli (IFN-gamma, IFN-beta, LPS). IRF8 deficiency in humans causes a severe primary immunodeficiency presenting as susceptibility to infections, complete or severe depletion of blood dendritic cells (DC) subsets, depletion of CD14(+) and CD16(+) monocytes and reduced numbers and impaired activity of NK cells. In genome-wide association studies (GWAS), sequence variants near IRF8 are significant risk factors for multiple chronic inflammatory diseases in humans including inflammatory bowel disease, lupus, rheumatoid arthritis, multiple sclerosis, and several others. Recent studies have cataloged all the genes bound by and transcriptionally activated by IRF8 in myeloid cells, either alone or in combination with other transcription factors (PU.1, IRF1, STAT1) at steady state and in response to pro-inflammatory stimuli. This IRF1/IRF8 regulome comprises immune pathways such as antigen processing and presentation pathways, expression of costimulatory molecules, cytokines and chemokines, response to stimuli such as cytokine receptors, pathogen-associated molecular pattern receptors, TLRs and nucleotide-binding oligomerization domain-like receptor signaling pathways, and small antiviral GTPases. Members of the IRF8/IRF1 regulome are over-represented amongst genes in which mutations cause primary immunodeficiencies, and are specifically enriched at GWAS loci associated with chronic inflammatory diseases in humans. These recent studies highlight a critical role of IRF8 in the activity of several immune cell types for protection against infections, but also in pathological inflammation associated with common human inflammatory conditions.

  • Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases
    Human Genetics, 2020
    Co-Authors: Sandra Salem, David Salem, Philippe Gros
    Abstract:

    The transcription factor IRF8 (ICSBP) is required for the development and maturation of myeloid cells (dendritic cells, monocytes, macrophages), and for expression of intrinsic anti-microbial function such as antigen capture, processing and presentation to lymphoid cells, and for activation of these cells in response to cytokines and pro-inflammatory stimuli (IFN-γ, IFN-β, LPS). IRF8 deficiency in humans causes a severe primary immunodeficiency presenting as susceptibility to infections, complete or severe depletion of blood dendritic cells (DC) subsets, depletion of CD14^+ and CD16^+ monocytes and reduced numbers and impaired activity of NK cells. In genome-wide association studies (GWAS), sequence variants near IRF8 are significant risk factors for multiple chronic inflammatory diseases in humans including inflammatory bowel disease, lupus, rheumatoid arthritis, multiple sclerosis, and several others. Recent studies have cataloged all the genes bound by and transcriptionally activated by IRF8 in myeloid cells, either alone or in combination with other transcription factors (PU.1, IRF1, STAT1) at steady state and in response to pro-inflammatory stimuli. This IRF1/IRF8 regulome comprises immune pathways such as antigen processing and presentation pathways, expression of costimulatory molecules, cytokines and chemokines, response to stimuli such as cytokine receptors, pathogen-associated molecular pattern receptors, TLRs and nucleotide-binding oligomerization domain-like receptor signaling pathways, and small antiviral GTPases. Members of the IRF8/IRF1 regulome are over-represented amongst genes in which mutations cause primary immunodeficiencies, and are specifically enriched at GWAS loci associated with chronic inflammatory diseases in humans. These recent studies highlight a critical role of IRF8 in the activity of several immune cell types for protection against infections, but also in pathological inflammation associated with common human inflammatory conditions.

  • the macrophage irf8 IRF1 regulome is required for protection against infections and is associated with chronic inflammation
    Journal of Experimental Medicine, 2016
    Co-Authors: David Langlais, Luis B Barreiro, Philippe Gros
    Abstract:

    IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by proinflammatory signals such as interferon-γ (IFN-γ). Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all of the genes bound by (cistromes) and transcriptionally activated by (regulomes) IRF8, IRF1, PU.1, and STAT1, including modulation of epigenetic histone marks. Of the seven binding combinations identified, two (cluster 1 [IRF8/IRF1/STAT1/PU.1] and cluster 5 [IRF1/STAT1/PU.1]) were found to have a major role in controlling macrophage transcriptional programs both at the basal level and after IFN-γ activation. They direct the expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and antimicrobial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immunodeficiencies and with loci associated with several inflammatory diseases in humans.

  • The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation
    Journal of Experimental Medicine, 2016
    Co-Authors: David Langlais, Luis B Barreiro, Philippe Gros
    Abstract:

    IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by proinflammatory signals such as interferon-γ (IFN-γ). Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all of the genes bound by (cistromes) and transcriptionally activated by (regulomes) IRF8, IRF1, PU.1, and STAT1, including modulation of epigenetic histone marks. Of the seven binding combinations identified, two (cluster 1 [IRF8/IRF1/STAT1/PU.1] and cluster 5 [IRF1/STAT1/PU.1]) were found to have a major role in controlling macrophage transcriptional programs both at the basal level and after IFN-γ activation. They direct the expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and antimicrobial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immunodeficiencies and with loci associated with several inflammatory diseases in humans.

  • a novel role for interferon regulatory factor 1 IRF1 in regulation of bone metabolism
    Journal of Cellular and Molecular Medicine, 2014
    Co-Authors: Sandra Salem, Ailian Li, Huifen Wang, Loan Nguyenyamamoto, David Goltzman, Janet E Henderson, Philippe Gros
    Abstract:

    Increased risk of bone fractures is observed in patients with chronic inflammatory conditions, such as inflammatory bowel disease and rheumatoid arthritis. Members of the Interferon Response Factor family of transcriptional regulators, IRF1 and IRF8, have been identified as genetic risk factors for several chronic inflammatory and autoimmune diseases. We have investigated a potential role for the IRF1 gene in bone metabolism. Here, we report that IRF1−/−mutant mice show altered bone morphology in association with altered trabecular bone architecture and increased cortical thickness and cellularity. Ex vivo studies on cells derived from bone marrow stimulated with Rank ligand revealed an increase in size and resorptive activity of tartrate-resistant acid-positive cells from IRF1−/− mutant mice compared with wild-type control mice. IRF1 deficiency was also associated with decreased proliferation of bone marrow-derived osteoblast precursors ex vivo, concomitant with increased mineralization activity compared with control cells. We show that IRF1 plays a role in bone metabolism and suggest that IRF1 regulates the maturation and activity of osteoclasts and osteoblasts. The altered bone phenotype of IRF1−/− mutants is strikingly similar to that of Stat1−/− mice, suggesting that the two interacting proteins play a critical enabling role in the common regulation of these two cell lineages.

Lanjuan Li - One of the best experts on this subject based on the ideXlab platform.

  • tagging single nucleotide polymorphisms in the IRF1 and irf8 genes and tuberculosis susceptibility
    PLOS ONE, 2012
    Co-Authors: Shiping Ding, Jianqin He, Tao Jiang, Lanjuan Li
    Abstract:

    Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3′UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35∼2.27, P = 0.002), 4.75 (95% CI 2.16∼10.43, P = 0.002) and 3.39 (95% CI 1.60∼7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P<0.01), which implied rs10514611 was a potential functional SNP site. Our results indicated that the IRF8 gene might participate in genetic susceptibility to tuberculosis in a Chinese population.

  • Tagging Single Nucleotide Polymorphisms in the IRF1 and IRF8 Genes and Tuberculosis Susceptibility
    PLOS ONE, 2012
    Co-Authors: Shiping Ding, Jianqin He, Tao Jiang, Lanjuan Li
    Abstract:

    Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3′UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35∼2.27, P = 0.002), 4.75 (95% CI 2.16∼10.43, P = 0.002) and 3.39 (95% CI 1.60∼7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P

Li Li - One of the best experts on this subject based on the ideXlab platform.

  • composition and transcription of all interferon regulatory factors irfs IRF1 11 in a perciform fish the mandarin fish siniperca chuatsi
    Developmental and Comparative Immunology, 2018
    Co-Authors: Zubair Ahmed Laghari, Li Li, Shan Nan Chen, Bei Huang, Ying Zhou
    Abstract:

    Interferon regulatory factors (IRFs) are a family of mediators in various biological processes including immune modulation of interferon (IFN) and proinflammatory cytokine expression. However, the data on the complete composition of IRFs is rather limited in teleost fish. In the present study, all IRF members, i.e. IRF1‒11 with two IRF4, IRF4a and IRF4b have been characterised in an aquaculture species of fish, the mandarin fish, Siniperca chuatsi, in addition to the previous report of IRF1, IRF2, IRF3 and IRF7 from the fish. These IRFs are constitutively expressed in various organs/tissues of the fish, and their expression can be induced following the stimulation of polyinosinic:polycytidylic acid (poly(I:C)) and the infection of infectious spleen and kidney necrosis virus (ISKNV), a viral pathogen of mandarin fish in aquaculture. The ISKNV infection induced the significant increase in the expression of some IRF genes, i.e. IRF2, IRF4a, IRF7, IRF9, IRF10 at 24 or 36 h post-infection (hpi) in spleen and head-kidney, and the significant increase of some other IRF genes, e.g. IRF1, IRF3, IRF4b, IRF5, IRF6, IRF8 at later stage of infection from 72, or 96, or even 120 hpi, which may imply the inhibitory effect of ISKNV on fish immune response. It is considered that the present study provides the first detailed analysis on all IRF members in an aquaculture species of fish, and can be served as the base for further investigation on the role of IRFs in teleost fish.

  • two type ii ifn members ifn γ and ifn γ related rel regulate differentially IRF1 and IRF11 in zebrafish
    Fish & Shellfish Immunology, 2017
    Co-Authors: Bai Ye Ruan, Zubair Ahmed Laghari, Shan Nan Chen, Bei Huang, Li Li
    Abstract:

    Abstract Two members of type II IFNs have been identified in fish, i.e. an IFN-γ gene as in other vertebrates and a unique IFN-γ related (IFN-γ rel) gene being solely present in fish. However, the signalling pathways involved in the down-stream signalling of type II IFNs in fish remains poorly described. In this study, the type II IFNs mediated IRF1 was investigated in zebrafish, and the true homologous gene of mammalian IRF1 in fish was revealed despite the report of so-called IRF1a and IRF1b in zebrafish. As revealed in overexpression analysis, zebrafish IFN-γ had a higher induction ability than IFN-γ rel in relation with the expression of IRF1. IFN-γ stimulated the expression level of STAT1a and also STAT1b, but they had opposite trends with the increase of time; enhancement of STAT1a waned after 12 h post injection of plasmids; whereas STAT1b expression increased continuously. Zebrafish IRF1 gene promoter contained several putative transcription factor binding sites, including GAS and NF-κB motifs. Luciferase assay revealed that the GAS site was essential in the IFN-γ triggered IRF1 expression. In contrast, IRF11 contained neither GAS nor NF-κB elements, and did not respond to IFN-γ induction. It is considered that STAT1a and STAT1b are structurally and functionally similar to STAT1α and STAT1β in mammal respectively, and that IRF11, although used to be nominated as IRF1a, is not the orthologue of mammalian IRF1, but IRF1b in zebrafish should be the orthologue.

Shiping Ding - One of the best experts on this subject based on the ideXlab platform.

  • tagging single nucleotide polymorphisms in the IRF1 and irf8 genes and tuberculosis susceptibility
    PLOS ONE, 2012
    Co-Authors: Shiping Ding, Jianqin He, Tao Jiang, Lanjuan Li
    Abstract:

    Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3′UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35∼2.27, P = 0.002), 4.75 (95% CI 2.16∼10.43, P = 0.002) and 3.39 (95% CI 1.60∼7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P<0.01), which implied rs10514611 was a potential functional SNP site. Our results indicated that the IRF8 gene might participate in genetic susceptibility to tuberculosis in a Chinese population.

  • Tagging Single Nucleotide Polymorphisms in the IRF1 and IRF8 Genes and Tuberculosis Susceptibility
    PLOS ONE, 2012
    Co-Authors: Shiping Ding, Jianqin He, Tao Jiang, Lanjuan Li
    Abstract:

    Genes encoding IRF1 and IRF8 protein have been proposed as candidate tuberculosis susceptibility genes. In order to elucidate whether the IRF1 and IRF8 variants were associated with tuberculosis susceptibility, we conducted a case-control study consisting of 495 controls and 452 ethnically matched cases with tuberculosis in a Chinese population. Seven haplotype tagging single-nucleotide polymorphisms (tagSNPs) (rs2057656; rs2706381; rs2070724; rs2070721; rs2549008; rs2549007; rs2706386) from HapMap database were analyzed, which provided an almost complete coverage of the genetic variations in the IRF1 gene. Fifteen tagSNPs (rs12924316; rs182511; rs305080; rs2292980; rs925994; rs424971; rs16939967; rs11117415; rs4843860; rs9926411; rs8064189; rs12929551; rs10514611; rs1044873; rs6638) were observed in the IRF8 gene. All these tagSNPs were genotyped by SNPstream genotyping and SNaPshot typing. None of the seven tagSNPs was individually associated with tuberculosis in the IRF1 gene. In the IRF8 gene, interestingly, we found that three tagSNPs (rs925994 and rs11117415 located in the intron region; rs10514611 located in the 3′UTR) were associated with risk of tuberculosis after Bonferroni correction. Per allele OR was 1.75 (95% CI 1.35∼2.27, P = 0.002), 4.75 (95% CI 2.16∼10.43, P = 0.002) and 3.39 (95% CI 1.60∼7.20, P = 0.015) respectively. Luciferase reporter gene assay showed that the construct that contained the non-risk allele C of rs10514611 showed significantly higher luciferase activity than did the risk T allele (P

Zubair Ahmed Laghari - One of the best experts on this subject based on the ideXlab platform.

  • composition and transcription of all interferon regulatory factors irfs IRF1 11 in a perciform fish the mandarin fish siniperca chuatsi
    Developmental and Comparative Immunology, 2018
    Co-Authors: Zubair Ahmed Laghari, Li Li, Shan Nan Chen, Bei Huang, Ying Zhou
    Abstract:

    Interferon regulatory factors (IRFs) are a family of mediators in various biological processes including immune modulation of interferon (IFN) and proinflammatory cytokine expression. However, the data on the complete composition of IRFs is rather limited in teleost fish. In the present study, all IRF members, i.e. IRF1‒11 with two IRF4, IRF4a and IRF4b have been characterised in an aquaculture species of fish, the mandarin fish, Siniperca chuatsi, in addition to the previous report of IRF1, IRF2, IRF3 and IRF7 from the fish. These IRFs are constitutively expressed in various organs/tissues of the fish, and their expression can be induced following the stimulation of polyinosinic:polycytidylic acid (poly(I:C)) and the infection of infectious spleen and kidney necrosis virus (ISKNV), a viral pathogen of mandarin fish in aquaculture. The ISKNV infection induced the significant increase in the expression of some IRF genes, i.e. IRF2, IRF4a, IRF7, IRF9, IRF10 at 24 or 36 h post-infection (hpi) in spleen and head-kidney, and the significant increase of some other IRF genes, e.g. IRF1, IRF3, IRF4b, IRF5, IRF6, IRF8 at later stage of infection from 72, or 96, or even 120 hpi, which may imply the inhibitory effect of ISKNV on fish immune response. It is considered that the present study provides the first detailed analysis on all IRF members in an aquaculture species of fish, and can be served as the base for further investigation on the role of IRFs in teleost fish.

  • two type ii ifn members ifn γ and ifn γ related rel regulate differentially IRF1 and IRF11 in zebrafish
    Fish & Shellfish Immunology, 2017
    Co-Authors: Bai Ye Ruan, Zubair Ahmed Laghari, Shan Nan Chen, Bei Huang, Li Li
    Abstract:

    Abstract Two members of type II IFNs have been identified in fish, i.e. an IFN-γ gene as in other vertebrates and a unique IFN-γ related (IFN-γ rel) gene being solely present in fish. However, the signalling pathways involved in the down-stream signalling of type II IFNs in fish remains poorly described. In this study, the type II IFNs mediated IRF1 was investigated in zebrafish, and the true homologous gene of mammalian IRF1 in fish was revealed despite the report of so-called IRF1a and IRF1b in zebrafish. As revealed in overexpression analysis, zebrafish IFN-γ had a higher induction ability than IFN-γ rel in relation with the expression of IRF1. IFN-γ stimulated the expression level of STAT1a and also STAT1b, but they had opposite trends with the increase of time; enhancement of STAT1a waned after 12 h post injection of plasmids; whereas STAT1b expression increased continuously. Zebrafish IRF1 gene promoter contained several putative transcription factor binding sites, including GAS and NF-κB motifs. Luciferase assay revealed that the GAS site was essential in the IFN-γ triggered IRF1 expression. In contrast, IRF11 contained neither GAS nor NF-κB elements, and did not respond to IFN-γ induction. It is considered that STAT1a and STAT1b are structurally and functionally similar to STAT1α and STAT1β in mammal respectively, and that IRF11, although used to be nominated as IRF1a, is not the orthologue of mammalian IRF1, but IRF1b in zebrafish should be the orthologue.