Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA277018 | ENA |
REPOSITORIES: ENA
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Project description:Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for the activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell. We used microarrays to explore the gene expression profiles differentially expressed in Francisella-infected bone marrow-derived macrophages (BMDMs) isolated from Irf1-/-, Ifnar1-/-, Aim2-/- and wild-type mice.
2015-03-04 | E-GEOD-66461 | biostudies-arrayexpress
Project description:Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for the activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell.
2015-03-04 | GSE66461 | GEO
Project description:Francisella are pathogenic bacteria whose virulence is linked to their ability to replicate within the host cell cytosol. Entry into the macrophage cytosol activates a host protective multimolecular complex called the inflammasome to release the proinflammatory cytokines IL-1 and IL-18 and trigger caspase-1 dependent cell death. Here we show that cytosolic Francisella induce a type I interferon (IFN) response that is essential for caspase-1 activation, inflammasome mediated cell death, and release of IL-1 and IL-18. Extensive type I IFN dependent cell death resulting in macrophage depletion occurs in vivo during Francisella infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria but not vacuole localized Salmonella or extracellular ATP. These results show the specific connection between type I IFN signaling and inflammasome activation, two sequential events triggered by recognition of cytosolic bacteria. To our knowledge, this is the first example of positive regulation of inflammasome activation. This connection underscores the importance of cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses. Keywords: murine macrophage response to Francisella tularensis subspecies novicida infection We analyzed a series of 18 MEEBO arrays on which were hybed RNA randomly amplified from bone marrow derived macrophages infected or not with WT Francisella tularensis subspecies novicida or a the mglA mutant strain GB2.
2007-05-23 | E-GEOD-7684 | biostudies-arrayexpress
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.
2018-04-27 | GSE110452 | GEO
Project description:Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1?/? MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis. RNA was isolated from RasV12 transformed NIH/3T3 cells (RasV12 cells) treated with 20?M U0126 or 500U/ml IFN-?, or left untreated, for 6 hours, triplicate biological samples (9 samples).
2014-11-13 | E-GEOD-49469 | biostudies-arrayexpress
Project description:The inflammasome initiates innate defense and inflammatory response by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It is comprised of an innate immune receptor/effector, pro-caspase-1 and a common adaptor molecule, ASC (apoptotic speck-containing protein with a CARD). Consistent with their pro-inflammatory function, inflammasome components including caspase-1, ASC and NLRP3, are known to exacerbate autoimmunity during experimental autoimmune encephalomyelitis (EAE) by enhancing IL-1 and IL-18 secretion in myeloid cells3-6. Here we show an unexpected function of a DNA-binding inflammasome effector, AIM2 (Absent in Melanoma 2)7-10, in restraining autoimmunity by performing EAE in both whole body and Treg-specific deletion of Aim2–/– mice. AIM2 is highly expressed by human and mouse Treg cells and it is essential to attenuate EAE. RNA-seq, biochemical and metabolic analyses revealed that AIM2 attenuates mTOR, Myc and immune-metabolic functions in both Treg cells isolated in vivo and Treg cells induced in vitro with TGF-. Importantly, we found AIM2 physically interacted with RACK1 in Treg cells to facility the PP2A/RACK1/Akt-mTOR signaling, which is identified as a central component downstream of AIM2 that controls Treg cell function and stability. While AIM2 is generally accepted as an inflammasome effector in myeloid cells, this report reveals a previously unappreciated T cell-intrinsic role of AIM2 in maintaining Treg cell function to restrain autoimmunity. This is achieved by diminishing Akt-mTOR signaling to regulate Treg stability under inflammation, and altering immune-metabolism in Treg cells.
2021-01-27 | PXD018638 | Pride
Project description:Innate immune sensing of influenza A virus (IAV) induces activation of various immune effector mechanisms including the NLRP3 inflammasome and programmed cell death pathways. Although type I IFNs are identified as key mediators of inflammatory and cell death responses during IAV infection, the involvement of various IFN-regulated effectors in facilitating these responses are less studied. Here, we demonstrate the role of interferon regulatory factor 1 (IRF1) in promoting NLRP3 inflammasome activation and cell death during IAV infection. IRF1 functions as a transcriptional regulator of Z-DNA binding protein 1 (ZBP1, also called as DLM1/DAI), a key molecule mediating IAV-induced inflammatory and cell death responses. Therefore, our study identified IRF1 as an upstream regulator of NLRP3 inflammasome and cell death during IAV infection and further highlights the complex and multilayered regulation of key molecules controlling inflammatory response and cell fate decisions during infections.
2017-12-07 | GSE103059 | GEO
Project description:Francisella are pathogenic bacteria whose virulence is linked to their ability to replicate within the host cell cytosol. Entry into the macrophage cytosol activates a host protective multimolecular complex called the inflammasome to release the proinflammatory cytokines IL-1 and IL-18 and trigger caspase-1 dependent cell death. Here we show that cytosolic Francisella induce a type I interferon (IFN) response that is essential for caspase-1 activation, inflammasome mediated cell death, and release of IL-1 and IL-18. Extensive type I IFN dependent cell death resulting in macrophage depletion occurs in vivo during Francisella infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria but not vacuole localized Salmonella or extracellular ATP. These results show the specific connection between type I IFN signaling and inflammasome activation, two sequential events triggered by recognition of cytosolic bacteria. To our knowledge, this is the first example of positive regulation of inflammasome activation. This connection underscores the importance of cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses. Keywords: murine macrophage response to Francisella tularensis subspecies novicida infection
2007-05-23 | GSE7684 | GEO
Project description:Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune receptor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators were largely intact in Aim2-deficient mice, however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with wild-type healthy mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer. We used microarrays to compare the transcriptome Aim2 deficent mice to wild type mice in colon tumor and colitis samples. Here were 12 mice in total, 3 for each genotype and tissue combination.
2015-07-15 | E-GEOD-69436 | biostudies-arrayexpress
Project description:Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1−/− MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis.
2014-11-13 | GSE49469 | GEO