Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-57253
PROVIDER: PRJNA246060 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1268060.fastq.gz | Fastqsanger.gz | |||
| SRR1268070.fastq.gz | Fastqsanger.gz | |||
| SRR1268080.fastq.gz | Fastqsanger.gz | |||
| SRR1268061.fastq.gz | Fastqsanger.gz | |||
| SRR1268071.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome
2019-05-14 | E-GEOD-57253 | ExpressionAtlas
Project description:Inflammasomes are intracellular innate immune sensors that respond to pathogen and damage-associated signals with the proteolytic cleavage of caspase-1, resulting in IL-1_ and IL-18 secretion and macrophage pyroptosis. The discovery that heterozygous gain-of-function mutations in NLRP3 lead to oversecretion of IL-1_ and cause the autoinflammatory disease spectrum Cryopyrin Associated Periodic Syndrome (CAPS), led to the successful use of IL-1 blocking therapies1. We found that a de novo missense mutation in the regulatory domain of the NLRC4 (IPAF, CARD12) inflammasome causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous production of the inflammasome-dependent cytokines IL-1² and IL-18 exceeding levels in CAPS patients. The NLRC4 mutation led to constitutive caspase-1 cleavage in transduced cells and enhanced spontaneous production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the autoinflammatory paradigm to include MAS and suggests novel targets for therapy.
2014-09-08 | GSE57253 | GEO
Project description:Inflammasomes are intracellular innate immune sensors that respond to pathogen and damage-associated signals with the proteolytic cleavage of caspase-1, resulting in IL-1_ and IL-18 secretion and macrophage pyroptosis. The discovery that heterozygous gain-of-function mutations in NLRP3 lead to oversecretion of IL-1_ and cause the autoinflammatory disease spectrum Cryopyrin Associated Periodic Syndrome (CAPS), led to the successful use of IL-1 blocking therapies1. We found that a de novo missense mutation in the regulatory domain of the NLRC4 (IPAF, CARD12) inflammasome causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous production of the inflammasome-dependent cytokines IL-1² and IL-18 exceeding levels in CAPS patients. The NLRC4 mutation led to constitutive caspase-1 cleavage in transduced cells and enhanced spontaneous production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the autoinflammatory paradigm to include MAS and suggests novel targets for therapy. Whole blood RNA-seq from seven timepoints of one patient with NLRC4-MAS as compared to five healthy pediatric controls, 7 NOMID patients with active disease prior to anakinra treatment and the same 7 NOMID patients with inactive disease after anakinra treatment. Please note that seven time points are chronologic time point. They are ordinal, in that "1" was drawn before "2", but the distance in time between points is not constant. Thus, time points 4 through 7 correspond to samples drawn while the patient was well AND on treatment. However there may be differences between 4 and 7 pertaining to the length of treatment, and for that reason any of these samples were not considered replicates.
2014-09-08 | E-GEOD-57253 | biostudies-arrayexpress
Project description:Short interspersed element (SINE) RNAs are upregulated by cellular stresses1 (heat shock, DNA damage and viral infection) and accumulate in human diseases (macular degeneration2, lupus3, and Alzheimer’s disease4). These transcripts activate inflammasomes5, a family of cytoplasmic multiprotein complexes that sense danger molecules and initiate innate immune responses by activating caspase-1-dependent cytokine production and inflammatory death6, but the molecular sensor of SINE RNAs is unknown. Here, we identify DDX17, a member of the DEAD box family of RNA helicases7, as a sensor of SINE RNAs requisite for inflammasome activation. Induction of caspase-1 cleavage and release of IL-1 and IL-18 by SINE RNAs requires dual recruitment of NLRP3 and NLRC4 but proceeds independent of NAIPs, immune sensors required for canonical NLRC4 activation by bacterial proteins8,9. Instead, SINE RNAs trigger DDX17–NLRC4 interaction, which licenses inflammasome activation. We also report increased levels of DDX17 protein and association of DDX17 and NLRC4 in the retinal pigmented epithelium (RPE) of human eyes with an advanced, untreatable form of age-related macular degeneration (AMD). Disrupting DDX17–NLRC4 signalling blocks SINE RNA-induced inflammasome activation in human RPE cells and RPE degeneration in an animal model of AMD. Our findings uncover a non-canonical mode of inflammasome activation by endogenous retrotransposon transcripts, and provide new potential targets for macular degeneration and potentially other diseases.
2022-06-09 | PXD016019 | Pride
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:The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe FDA-approved drug, specifically inhibits the NLRP3 inflammasome, but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not the NLRC4 inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.
2024-07-25 | PXD054126 | Pride
Project description:Bacterial flagellin is a dominant innate immune activator of the intestine. Therefore, we examined the role of the intracellular flagellin receptor, NLRC4, in protecting the gut and/or driving inflammation. In accord with NLRC4 acting via transcription-independent pathways, loss of NLRC4 did not reduce the rapid robust changes in intestinal gene expression induced by flagellin administration. Loss of NLRC4 did not alter basal intestinal homeostasis nor predispose mice to development of colitis upon administration of an anti-IL-10R monoclonal antibody. However, in response to epithelial injury induced by dextran sulfate sodium (DSS), loss of NLRC4 resulted in more severe disease indicating a role for NLRC4 in protecting the gut. Moreover, loss of NLRC4 resulted in increased mortality in response to flagellate, but not aflagellate Salmonella infection. Thus, despite not being involved in rapid intestinal gene remodeling upon detection of flagellin, NLRC4-mediated inflammasome activation protects mice from mucosal and systemic challenges Flagellin (FliC) from WT Salmonella enterica serovar Typhimurium (SL3201, fljB–) was purified through sequential cation and anion-exchange chromatography and purity was verified as previously described 4. WT, T5KO, N4KO and T5/N4-DKO mice (n=6) were given either 0.2 mL PBS or flagellin (10μg/mouse in 0.2 mL PBS) intraperitoneally. After 1h, mice were euthanized and colon was taken and stored in RNAlater (Invitrogen) for 1 day. Total mRNA was isolated from colonic tissues using TRIzol (Invitrogen) and purified using the RNeasy® Plus Mini kit (Qiagen) according to the manufacturer’s instructions
2012-01-01 | E-GEOD-34492 | biostudies-arrayexpress
Project description:Bacterial flagellin is a dominant innate immune activator of the intestine. Therefore, we examined the role of the intracellular flagellin receptor, NLRC4, in protecting the gut and/or driving inflammation. In accord with NLRC4 acting via transcription-independent pathways, loss of NLRC4 did not reduce the rapid robust changes in intestinal gene expression induced by flagellin administration. Loss of NLRC4 did not alter basal intestinal homeostasis nor predispose mice to development of colitis upon administration of an anti-IL-10R monoclonal antibody. However, in response to epithelial injury induced by dextran sulfate sodium (DSS), loss of NLRC4 resulted in more severe disease indicating a role for NLRC4 in protecting the gut. Moreover, loss of NLRC4 resulted in increased mortality in response to flagellate, but not aflagellate Salmonella infection. Thus, despite not being involved in rapid intestinal gene remodeling upon detection of flagellin, NLRC4-mediated inflammasome activation protects mice from mucosal and systemic challenges
2012-01-01 | GSE34492 | GEO
Project description:Inflammatory bowel disease (IBD) is a challenging condition with limited therapeutic options. Inflammasome activation is integral to IBD pathogenesis, although the molecular instigators of its activation remain obscure. Here, we establish that telomere dysfunction activates the Yap1 transcriptional co-activator through pATM/c-Abl, which up-regulates expression of microbial receptors Nlrc4 and Nlrc5 and the cytokine pre-IL-18. Microbial engagement of these cytosolic receptors leads to production of mature IL-18, recruiting T cells and other immunocytes which secrete IFN-gamma to drive classical IBD pathology. Genotoxic stress per se (ionizing radiation) can also drive inflammasome activation. Alleviation of IBD pathology can be achieved via telomerase reactivation in intestinal epithelium, antibiotic treatment or pharmacological inhibition of Yap1 - reducing Nlrc4/5 expression as well as IL-18 and IFN-gamma production. Thus, telomere dysfunction-induced inflammasome activation identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating potential novel therapeutic strategies for prevention and disease management.
2020-01-01 | GSE108902 | GEO
Project description:IRF8 regulates transcription of Naips for NLRC4 inflammasome activation
| PRJNA433766 | ENA