The macrophage IRF8-IRF1 regulome is required for protection against infections, and is associated with chronic inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE77886 | GEO | 2016/03/03
SECONDARY ACCESSION(S): PRJNA311948
REPOSITORIES: GEO
Similar Datasets
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 proinflammatory signals such as interferon-? (IFN-?). 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 inIRF8andIRF1mutant 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-? 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.
| S-EPMC4821649 | biostudies-literature
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:The macrophage IRF8-IRF1 regulome is required for protection against infections, and is associated with chronic inflammation
| PRJNA311948 | ENA
Project description: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.
| S-EPMC3412841 | biostudies-literature
Project description:The encapsulated bacteria Streptococcus pneumoniae, Neisseria meningitis, Haemophilus influenzae, and Streptococcus agalactiae (Group B Streptococcus) have been responsible for the majority of severe infections in children for decades, specifically bacteremia and meningitis. Isolates which cause invasive disease are usually surrounded by a polysaccharide capsule, which is a major virulence factor and the key antigen in protective protein-polysaccharide conjugate vaccines. Protection against these bacteria is largely mediated via polysaccharide-specific antibody and complement, although the contribution of these and other components, and the precise mechanisms, vary between species and include opsonophagocytosis and complement-dependent bacteriolysis. Further studies are required to more precisely elucidate mechanisms of protection against non-type b H. influenzae and Group B Streptococcus.
| S-EPMC6255856 | biostudies-other
Project description:Intestinal inflammation is the central pathological feature of colitis and the inflammatory bowel diseases. These syndromes arise from unidentified environmental factors. We found that recurrent nonlethal gastric infections of Gram-negative Salmonella enterica Typhimurium (ST), a major source of human food poisoning, caused inflammation of murine intestinal tissue, predominantly the colon, which persisted after pathogen clearance and irreversibly escalated in severity with repeated infections. ST progressively disabled a host mechanism of protection by inducing endogenous neuraminidase activity, which accelerated the molecular aging and clearance of intestinal alkaline phosphatase (IAP). Disease was linked to a Toll-like receptor 4 (TLR4)-dependent mechanism of IAP desialylation with accumulation of the IAP substrate and TLR4 ligand, lipopolysaccharide-phosphate. The administration of IAP or the antiviral neuraminidase inhibitor zanamivir was therapeutic by maintaining IAP abundance and function.
| S-EPMC5824721 | biostudies-other
Project description:The fatal impairment of the intestinal mucosal barrier of chicks caused by Salmonella significantly resulting economic losses in the modern poultry industry. Probiotics are recognized for beneficially influencing host immune responses, promoting maintenance of intestinal epithelial integrity, antagonistic activity against pathogenic microorganisms and health-promoting properties. Some basic studies attest to probiotic capabilities and show that Lacticaseibacillus rhamnosus could protect intestinal mucosa from injury in animals infected with Salmonella Typhimurium. However, the mechanisms underlying its protective effects in chicks are still not fully understood. Here, we used the chick infection model combined with histological, immunological, and molecular approaches to address this question. The results indicated that L. rhamnosus significantly reduced the diarrhea rate and increased the daily weight gain and survival rate of chicks infected with S. Typhimurium. Furthermore, we found that L. rhamnosus markedly improved the immunity of gut mucosa by reducing apoptotic cells, hence effectively inhibiting intestinal inflammation. Notably, pre-treatment chicks with L. rhamnosus balanced the expression of interleukin-1β and interleukin-18, moderated endotoxin and D-lactic acid levels, and expanded tight junction protein levels (Zonula occluden-1 and Claudin-1), enhanced the function of the intestinal mucosal epithelial cells. Additionally, investigations using full-length 16S rRNA sequencing also demonstrated that L. rhamnosus greatly weakened the adhesion of Salmonella, the mainly manifestation is the improvement of the diversity of intestinal microbiota in infected chicks. Collectively, these results showed the application of L. rhamnosus against Salmonella fatal infection by enhancing barrier integrity and the stability of the gut microbiota and reducing inflammation in new hatch chicks, offering new antibiotic alternatives for farming animals.
| S-EPMC9411107 | biostudies-literature
Project description:Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human enteroviruses including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1) predominantly induce type III interferons (IFN-?1 and IFN-?2/3), rather than type I interferons (IFN-? and IFN-?), in cultured human normal and cancerous intestine epithelial cells (IECs), mouse intestine tissues, and human clinical intestine specimens. Mechanistic studies demonstrated that IFN-? production is induced upon enterovirus infection through the Toll-like receptor 3/interferon regulatory factor 1 (TLR3/IRF1) signaling pathway in IECs. In turn, the supplementation of IFN-? subsequently induces intrinsically antiviral responses against enterovirus replication. Notably, intraperitoneal injection in neonatal C57BL/6J mice with mouse recombinant IFN-?2 protein represses EV71 replication and protects mice from viral lethal effects. Altogether, these results revealed a distinct mechanism by which the host elicited immune responses against enterovirus infections in intestine through activating the TLR3/IRF1/type III IFN axis. The new findings would provide an antiviral strategy for the prevention and treatment of enterovirus infections and associated diseases.IMPORTANCE Enterovirus infections are significant sources of human diseases and public health risks worldwide, but little is known about the mechanism of innate immune response in host intestine epithelial surface during the viral replication. We reported the epithelial immune response in cultured human normal and cancerous cells (IECs), mouse tissues, and human clinical intestine specimens following infection with enterovirus 71. The results mechanistically revealed type III interferons (IFN-?1 and IFN-?2/3), rather than type I interferons (IFN-? and IFN-?), as the dominant production through TLR3/IRF1 signaling upon multiple human enterovirus infection, including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1). IFN-? subsequently induced antiviral activity against enterovirus replication in vitro and in vivo. These studies uncovered the role of the novel process of type III IFN production involved in the TLR3/IRF1 pathway in host intestine upon enterovirus infection, which highlighted a regulatory manner of antiviral defense in intestine during enterovirus infection.
| S-EPMC7683398 | biostudies-literature
Project description:BackgroundThe innate immune system recalls a challenge to adapt to a secondary challenge, a phenomenon called trained immunity. Training involves cellular metabolic, epigenetic and functional reprogramming, but how broadly trained immunity protects from infections is unknown. For the first time, we addressed whether trained immunity provides protection in a large panel of preclinical models of infections.MethodsMice were trained and subjected to systemic infections, peritonitis, enteritis, and pneumonia induced by Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Citrobacter rodentium, and Pseudomonas aeruginosa. Bacteria, cytokines, leukocytes, and hematopoietic precursors were quantified in blood, bone marrow, and organs. The role of monocytes/macrophages, granulocytes, and interleukin 1 signaling was investigated using depletion or blocking approaches.ResultsInduction of trained immunity protected mice in all preclinical models, including when training and infection were initiated in distant organs. Trained immunity increased bone marrow hematopoietic progenitors, blood Ly6Chigh inflammatory monocytes and granulocytes, and sustained blood antimicrobial responses. Monocytes/macrophages and interleukin 1 signaling were required to protect trained mice from listeriosis. Trained mice were efficiently protected from peritonitis and listeriosis for up to 5 weeks.ConclusionsTrained immunity confers broad-spectrum protection against lethal bacterial infections. These observations support the development of trained immunity-based strategies to improve host defenses.
| S-EPMC7653089 | biostudies-literature