Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA311950 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3167110_1.fastq.gz | Fastqsanger.gz | |||
| SRR3167110_2.fastq.gz | Fastqsanger.gz | |||
| SRR3167111_1.fastq.gz | Fastqsanger.gz | |||
| SRR3167111_2.fastq.gz | Fastqsanger.gz | |||
| SRR3167112_1.fastq.gz | Fastqsanger.gz |
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Project description:The macrophage IRF8-IRF1 regulome is required for protection against infections, and is associated with chronic inflammation
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Project description:The macrophage IRF8-IRF1 regulome is required for protection against infections, and is associated with chronic inflammation (ChIP-Seq)
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Project description:IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by pro-inflammatory signals such as interferon gamma. 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 the genes bound by (cistromes) and transcriptionally activated (regulomes) by IRF8, IRF1, PU.1 and STAT1 including modulation of epigenetic histone marks. Of seven binding combinations identified, two (cluster 1: IRF8/IRF1/STAT1/PU.1; cluster 5: IRF1/STAT1/PU.1) were found to have a major role in controlling macrophage transcriptional programs both at basal level and following IFNγ activation. They direct expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and anti-microbial 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 immuno-deficiencies, and with loci associated for several inflammatory diseases in humans.
2016-03-07 | GSE77885 | GEO
Project description:IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by pro-inflammatory signals such as interferon gamma. 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 the genes bound by (cistromes) and transcriptionally activated (regulomes) by IRF8, IRF1, PU.1 and STAT1 including modulation of epigenetic histone marks. Of seven binding combinations identified, two (cluster 1: IRF8/IRF1/STAT1/PU.1; cluster 5: IRF1/STAT1/PU.1) were found to have a major role in controlling macrophage transcriptional programs both at basal level and following IFNγ activation. They direct expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and anti-microbial 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 immuno-deficiencies, and with loci associated for several inflammatory diseases in humans.
2016-03-07 | GSE77884 | GEO
Project description:Inflammasome activation is critical for host defense against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes. IRF8 governs the transcription of Naips to allow detection of flagellin or T3SS proteins to mediate NLRC4 inflammasome activation. Furthermore, we found that IRF8 confers protection against bacterial infection in vivo, owing to its role in inflammasome-dependent cytokine production and pyroptosis. Altogether, our findings suggest that IRF8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection.
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Project description:Chronic intestinal inflammation produce dysplasia more frequently than the normal population. The therapies protect against these changes, but do not rule out dysplasia. It is not known the effect of different therapies protection.
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Project description:High macrophage infiltration in cancer is associated with reduced survival in animal models and in patients. This reflects a shift in the macrophage response from a tumor-suppressive to tumor-supportive program governed by transcriptional events regulated by the inflammatory milieu. Although several transcription factors are known to drive a pro-metastatic program, those that govern an anti-metastatic program are less understood. Interferon regulatory factor-8 (IRF8) is integral for macrophage responses against infections. Using a genetic loss-of-function approach, we tested the hypothesis that IRF8 expression in macrophages governs their capacity to inhibit metastasis. We found that: 1) metastasis was significantly increased in mice with IRF8-deficient macrophages; 2) IRF8-deficient macrophages displayed a neutrophil-like program enriched for metastasis-associated genes; and 3) lower IRF8 expression correlated with reduced survival in human breast cancer and melanoma with high or low macrophage infiltration. These data demonstrate a previously unrecognized role for IRF8 in macrophage biology to control metastasis.
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Project description:Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is the anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron storage, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this iron withholding reduces the iron available to developing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (Hamp) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. Hamp has antimicrobial activity and is part of the type II acute phase response. It is also thought to play a critical regulatory role in the sequestration of iron in the context of ACD. We report that mice with deficiencies in the hemochromatosis gene product, Hfe, mount a general inflammatory response, but lack appropriate Hamp expression and fail to develop hyposideremia. These data suggest a previously unidentified role for Hfe in innate immunity and ACD.
2004-03-15 | E-MEXP-95 | biostudies-arrayexpress
Project description:Analysis of transcriptional response to Plasmodium berghei ANKA infection in cerebral malaria susceptible C57BL/6 mouse brains as well as cerebral malaria resistant BXH2 mice which carry a severe hypomorphic Irf8-R294C allele. Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a loss-of-function allele at Irf8 (Irf8-R294C) that causes susceptibility to infection with intracellular pathogens, including Mycobacterium tuberculosis. We report that XH2 are completely resistant to the development of cerebral malaria following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes up-regulated by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes confers protection against experimental cerebral malaria. We also report strong overlap between genes bound and regulated by IRF8 during cerebral malaria and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. In summary, this work defines a common core of IRF8-bound genes forming a critical inflammatory host-response network. Comparison of whole brain transcript profiles for wildype C57BL/6 mice versus severely hypomorphic Irf8-R294C BXH2 mice following experimental infection with Plasmodium berghei ANKA (d7). Baseline (d0) profiles are also compared. Pleaes note that each sample record represents 2-4 replicates and sample data table contains mean, standard error of the mean (SEM), and quality for the replicates. The non_normalized data matrix contains raw data for each replicate (total 12 samples).
2015-01-16 | E-GEOD-65036 | biostudies-arrayexpress
Project description:As critical executors of the immune system, neutrophils provide an immediate inflammatory response for the clearance of debris and microbes, which is essential for the protection of health. Developmentally, neutrophils and macrophages share common progenitors, whose fate is tightly controlled by transcriptional programs. Dysregulation of these programs causes severe hematological disorders, including neutropenia, neutrophilia, leukemia, and inflammatory disorders. However, the mechanisms underlying the generation of neutrophils through these programs are poorly understood. Here, we revealed that Ikzf1 and Myb were enriched in neutrophils. Overactivation of Ikzf1 promoted neutrophil generation while suppressing macrophage emergence. Conversely, the simultaneous loss of Ikzf1 and Myb, but not the individual mutations, drastically impaired neutrophil production and enlarged the macrophage pool in both zebrafish and mice. Mechanistically, Ikzf1 and Myb formed a complex that targeted irf8 and induced the expression of a long non-coding RNA (lncRNA), irf8-2, through a novel regulatory element. LncRNA irf8-2 biased neutrophil commitment by modulating irf8 dosage via Zfp36l1. The deletion of irf8-2 resulted in defective neutrophil development and enhanced macrophage production. However, a partial ratio of neutrophils and macrophages was restored when Ikzf1, Myb, and Irf8 were all compromised. Overall, our study reveals that Ikzf1 and Myb cooperatively bias neutrophil development against Irf8 via the lncRNA irf8-2 and Zfp36l. This study provides novel insights into the conserved molecular balance between neutrophil and macrophage development during myelopoiesis, with potential implications for understanding and treating myeloid disorders.
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