Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA97341 | ENA |
REPOSITORIES: ENA
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Project description:Gasdermin-D (GSDMD) is cleaved by caspase-1/4/11 in response to canonical and non-canonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms membrane pores, resulting in IL-1β secretion, pyroptotic cell death and inflammatory pathologies including periodic fever syndromes and septic shock â a plague on modern medicine. The transcriptional machinery that drives the expression of GSDMD is unknown. Here we show that IRF2, a member of the interferon-regulatory factor (IRF) family, is essential for the transcriptional activation of GSDMD. A forward genetic screen with ethyl-N-nitrosourea (ENU)-mutagenized mice unequivocally linked IRF2 to inflammasome signaling. Indeed, GSDMD transcript levels were highly attenuated in Irf2â/â macrophages upon Irf2 deficiency in macrophages, endothelial cells, and multiple organs, corresponding to attenuated IL-1β secretion and inhibited pyroptosis. Mechanistically, IRF2 binds a previously uncharacterized site within the GSDMD promoter to directly drive GSDMD transcription for execution of pyroptosis in response to canonical and non-canonical inflammasome activation. Our data illuminate a prominent transcriptional mechanism for the expression of GSDMD, a key mediator of inflammatory pathologies.
2019-05-21 | GSE130195 | GEO
Project description:This study demonstrates that TS5-p45 induces endothelial cell (EC) apoptosis in a caspase-dependent manner via its cell surface receptor Nucleolin (NCL). To unravel how this apoptosis mechanism is induced in ECs, we performed RNA-seq using TS5-p45-treated ECs. Transcriptional changes under TS5-p45 treatment was further evaluated to highlight some of the caspase-dependent apoptosis-inducing and -suppressing genes which are altered in favor of apoptosis.
2022-03-02 | GSE191049 | GEO
Project description:The proposed ODE model describes dynamics of IFNalpha-induced signaling in Huh7.5 cells for a time scale up to 32 hours after stimulation with IFNalpha. The model consists of an IFN receptor model, formation/degradation and cytoplasmic/nuclear shuttling of STAT1-homodimers, STAT1-STAT2-heterodimers and STAT1-STAT2-IRF9 (ISGF3) complexes. On top, formation of feedback proteins STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3 and IRF2 and corresponding influences on IFNalpha signaling dynamics was incorporated. The model was calibrated by dose response and time course measurements over 32 hours as well as time courses for USP18 inhibition and overexpression experiments. As a special focus, the model is able to describe dose-dependent sensitization and desensitization of IFNalpha signaling in form of double treatment experiments at 0h and 24h.
2024-09-02 | BIOMD0000000959 | BioModels
Project description:MiR-221 overexpression leads to activation of apoptosis, growth arrest and reduced invasivness in PCa cells. Interaction of miR-221 with potential target genes was analyzed by a genome wide expression profiling.. Regulation of selected genes and proteins identified in the gene array analysis was confirmed by Real Time RT-PCR assay (IRF1, IRF2 SOCS3, STAT1), and Western Blotting. In total, 282 genes were upregulated and 64 downregulated based on a more than 2-fold difference to untransfected PC-3 cells. Regulated genes are involved in apoptosis, hemostasis, oxidative stress response, tumorigenesis and inflammation. We confirmed dysregulation of IRF-2 SOCS3, STAT1,IRF9. These results indicate that miR-221 overexpression might lead to activation of the JAK/STAT pathway and downregulation of miR-221 might contribute to tumorigenesis in PCa cells. pre-miR-221 transfected PC-3 cells vs unstimulated control cells - total samples analysed are 4.
2014-03-27 | E-GEOD-45627 | biostudies-arrayexpress
Project description:Long noncoding RNAs (lncRNAs) have emerged as novel regulators of macrophage biology and related inflammatory cardiovascular diseases. However, studies focused on lncRNAs in human macrophage subtypes, particularly human lncRNAs that are not conserved in rodents, are limited. Through RNA-seq of human monocyte-derived macrophages, we identified Suppressor of Inflammatory Macrophage Apoptosis lncRNA (SIMALR), a human macrophage-specific long intergenic noncoding RNA, to be highly induced in LPS/IFNγ-stimulated macrophages. Treatment of LPS/IFNγ stimulated THP1 human macrophages with SIMALR antisense oligonucleotides induced apoptosis of inflammatory macrophages, as shown by increased protein expression of cleaved PARP, caspase 9, caspase 3, and Annexin V+. RNA-seq of control versus SIMALR knockdown in LPS/IFNγ-stimulated human monocyte derived macrophages showed NTN1 to be significantly decreased upon SIMALR knockdown. As expected, NTN1 knockdown in LPS/IFNγ-stimulated macrophages induced apoptosis. This apoptotic phenotype was attenuated by adding recombinant NTN1 after SIMALR knockdown. Furthermore, NTN1 promoter-luciferase reporter activity was increased in HEK293T cells treated with lentiviral overexpression of SIMALR. NTN1 promoter activity is known to require HIF1α. RNA immunoprecipitation and microscopy studies suggest that SIMALR may interact with HIF1α to regulate NTN1 transcription, thereby regulating apoptosis of macrophages. In translational studies, SIMALR was found to be expressed in macrophages in human carotid atherosclerotic plaques of symptomatic patients. SIMALR is a non-conserved, human macrophage lincRNA expressed in human atherosclerosis that regulates macrophage apoptosis. SIMALR partners with HIF1α to regulate NTN1, which is a known macrophage survival factor. This work illustrates the importance of interrogating the functions of non-conserved human lincRNAs and exploring their translational and therapeutic potential in human atherosclerosis.
2022-11-23 | GSE212381 | GEO
Project description:Using microarray gene expression profiling of liver RNA samples rerived from IRF2+/+ and IRF2-/- mice treated with saline or LPS, we identified >40 genes that were significantly down-regulated in IRF2 -/- mice, including STAT3 which has been reported to regulate apoptosis. Keywords: compound treatment design We compared gene expression in IRF2+/+ and IRF2-/- mice treated with Saline or LPS for 3 or 6 hours. Two repeats were done for the LPS treatments. The total number of arrays is 6.
2007-09-01 | E-GEOD-5907 | biostudies-arrayexpress
Project description:Human macrophages secrete extracellular vesicles loaded with numerous immunoregulatory proteins. Here we employed high throughput quantitative proteomics to characterize the modulation of vesicle-mediated protein secretion during non-canonical caspase-4/5-dependent inflammasome activation. We show that human macrophages activate robust caspase-4- dependent extracellular vesicle secretion upon transfection of LPS, and this process is also partially dependent on NLRP-3 and caspase-5. Similar effect occurs with delivery of the LPS with E. coli-derived outer membrane vesicles. Moreover, sensitization of the macrophages through TLR4 prior to LPS transfection dramatically augments the EV-mediated protein secretion. Our data demonstrate that this process differs significantly from ATP-induced vesiculation, and is dependent on autocrine interferon signal associated with TLR4 activation. TLR4 activation preceding the non-canonical inflammasome activation significantly enhances vesicle-mediated secretion of inflammasome components caspase-1, ASC and lytic cell death effectors GSDMD, MLKL and NINJ1, suggesting that inflammatory EV transfer may exert paracrine effects in recipient cells. Moreover, using bioinformatic methods, we identify 15-deoxy-delta-12,14-prostaglandin J2 and parthenolide as inhibitors of caspase-4-mediated inflammation and vesicle secretion, indicating potential new therapeutic potential of these anti-inflammatory drugs.
2022-12-01 | PXD033002 | Pride
Project description:MiR-221 overexpression leads to activation of apoptosis, growth arrest and reduced invasivness in PCa cells. Interaction of miR-221 with potential target genes was analyzed by a genome wide expression profiling.. Regulation of selected genes and proteins identified in the gene array analysis was confirmed by Real Time RT-PCR assay (IRF1, IRF2 SOCS3, STAT1), and Western Blotting. In total, 282 genes were upregulated and 64 downregulated based on a more than 2-fold difference to untransfected PC-3 cells. Regulated genes are involved in apoptosis, hemostasis, oxidative stress response, tumorigenesis and inflammation. We confirmed dysregulation of IRF-2 SOCS3, STAT1,IRF9. These results indicate that miR-221 overexpression might lead to activation of the JAK/STAT pathway and downregulation of miR-221 might contribute to tumorigenesis in PCa cells.
2014-03-27 | GSE45627 | GEO
Project description:Using ChIP-Seq analysis we define genes induced in macrophages through transcriptional activation by STAT1 and search for the gain of function in mutant Stat1Y701F compared to the Stat1-/- mice.
2016-01-25 | E-MTAB-3597 | biostudies-arrayexpress