Select hyperactivating NLRP3 ligands enhance the Th1/Th17-inducing potential of human type 2 conventional dendritic cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE162407 | GEO | 2020/12/02
REPOSITORIES: GEO
Similar Datasets
Project description:The innate immune system recognizes nucleic acids as a signature of microbial infection and initiates host-protective responses, including the production of type I IFN and proinflammatory cytokines. Z-DNA binding protein 1 (ZBP1, also known as DLM-1 or DAI) was previously identified as a dsDNA binding protein, triggering DNA-mediated activation of innate immune responses. However, mice or cells lacking ZBP1 produce normal levels of type I IFN in response to dsDNA. Therefore, the classification of ZBP1 as a true DNA sensor remains to be resolved. Here, we report that the single stranded RNA virus, influenza A virus (IAV) is a trigger of the cytosolic sensor ZBP1. Sensing of IAV infection by ZBP1 engages a novel NLRP3 inflammasome pathway that is not defined by the conventions of the canonical and non-canonical NLRP3 inflammasome pathways. Surprisingly, IAV-induced cell death was not prevented by the absence of the NLRP3 inflammasome. Instead, we identified parallel contributions from pyroptosis, necroptosis and apoptosis in the execution of ZBP1-dependent cell death, mediated by the kinase RIPK3. Overall, the ability of ZBP1 to sense IAV infection signifies a point of divergence for IAV-induced programmed cell death pathways and inflammasome activation. We used microarrays to explore the gene expression profiles differentially expressed in influenza-infected bone marrow derived macrophages (BMDM) isolated from Ifnar1-/- and wild-type mice.
2016-08-11 | E-GEOD-77611 | biostudies-arrayexpress
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:Endothelial cell dysfunction plays an essential role in the process of cardiac ischemia-reperfusion (I/R) injury. Mitochondria damage, which can trigger inflammasome activation and subsequent pyroptosis, perturbs endothelial homeostasis, leading to aggravated cardiac I/R injury. Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effect on I/R injury via its different S1P receptors. However, the effect of EC-expressing S1P receptors on endothelial dysfunction, mitochondrial damage-induced inflammasome activation and consequent pyroptosis during cardiac I/R injury remain unclear. Our findings suggest a pivotal role of EC-expressing S1PR2 to control EC mitochondrial homeostasis and demonstrate that S1PR2-meidated mitochondrial dysfunction can trigger inflammasome activation and pyroptosis in ECs, which significantly influences inflammatory responses and heart injuries following I/R.
2024-07-25 | GSE245987 | GEO
Project description:Endothelial cell dysfunction plays an essential role in the process of cardiac ischemia-reperfusion (I/R) injury. Mitochondria damage, which can trigger inflammasome activation and subsequent pyroptosis, perturbs endothelial homeostasis, leading to aggravated cardiac I/R injury. Sphingosine 1-phosphate (S1P), a bioactive lipid molecule, exerts multifaceted effect on I/R injury via its different S1P receptors. However, the effect of EC-expressing S1P receptors on endothelial dysfunction, mitochondrial damage-induced inflammasome activation and consequent pyroptosis during cardiac I/R injury remain unclear. Our findings suggest a pivotal role of EC-expressing S1PR2 to control EC mitochondrial homeostasis and demonstrate that S1PR2-meidated mitochondrial dysfunction can trigger inflammasome activation and pyroptosis in ECs, which significantly influences inflammatory responses and heart injuries following I/R.
2024-07-25 | GSE245988 | GEO
Project description:The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation, but little is known concerning atrophy and its underlying mechanisms in denervated muscle to date. Here, we reported that activated NOD-like receptor protein 3 (NLRP3) inflammasome with pyroptotic cell death occurred in denervated gastrocnemius in the mouse model of sciatic denervation. This damage causes interleukin 1 beta (IL-1β) release，facilitating the ubiquitin proteasome system (UPS) activation, which was responsible for muscle proteolysis. Conversely, genetic knock-out of muscular NLRP3 inhibited the pyroptosis-associated protein expression and ameliorate muscle atrophy significantly. Meanwhile, co-treatment with shRNA-NLRP3, also remarkably attenuated NLRP3 inflammasome activator (NIA)-induced C2C12 myotube pyroptosis and atrophy. Interestingly, we also observed a correlation between NLRP3 inflammasome activation and muscular apoptosis possibly via caspase 1 mediation after denervation. This work for the first time elucidates on the roles and mechanisms of NLRP3 inflammasome in skeletal muscle atrophy during denervation and suggests the potential contribution to the pathogenesis of neuromuscular diseases.
2022-12-29 | GSE201133 | GEO
Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.
2023-09-18 | GSE217363 | GEO
Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.
2019-10-03 | PXD014828 | Pride
Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).
2014-07-01 | E-GEOD-58959 | biostudies-arrayexpress
Project description:Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that exacerbate IL-1 production. Although these are gain-of-function variants, the exact regulatory mechanism of the NLRP3-inflammasome in CAPS is not yet well understood. Despite being considered a hypersensitive inflammasome triggered by cell priming, patients with CAPS and animal models of the disease may present inflammatory flares even in the absence of identifiable external triggers. Herein, we found that CAPS-associated variants result in constitutively active NLRP3-inflammasome, which induce an increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4A. The constitutively active NLRP3-inflammasome was blocked by MCC950 and was dependent on NLRP3 expression level, further regulated by deubiquitination. Additionally, we determined that the activation of the NF-B pathway with lipopolysaccharide or other endogenous molecules (palmitate, S100A9, IL-6) further modulated the activation of the NLRP3-inflammasome in CAPS, thus expanding the repertoire of molecules secreted from patients’ macrophages involved in disease pathogenesis. NLRP3-inflammasomes with CAPS-associated variants mainly affected the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1β production. These findings demonstrate that NLRP3 variants causing CAPS form a constitutively active inflammasome that induces basal pyroptosis and IL-18 release without cell priming, favouring the host's innate defense against pathogens while also tempering the onset of IL-1β–dependent inflammatory episodes through immunometabolism modulation.
2023-12-13 | GSE246713 | GEO
Project description:The innate immune system recognizes nucleic acids as a signature of microbial infection and initiates host-protective responses, including the production of type I IFN and proinflammatory cytokines. Z-DNA binding protein 1 (ZBP1, also known as DLM-1 or DAI) was previously identified as a dsDNA binding protein, triggering DNA-mediated activation of innate immune responses. However, mice or cells lacking ZBP1 produce normal levels of type I IFN in response to dsDNA. Therefore, the classification of ZBP1 as a true DNA sensor remains to be resolved. Here, we report that the single stranded RNA virus, influenza A virus (IAV) is a trigger of the cytosolic sensor ZBP1. Sensing of IAV infection by ZBP1 engages a novel NLRP3 inflammasome pathway that is not defined by the conventions of the canonical and non-canonical NLRP3 inflammasome pathways. Surprisingly, IAV-induced cell death was not prevented by the absence of the NLRP3 inflammasome. Instead, we identified parallel contributions from pyroptosis, necroptosis and apoptosis in the execution of ZBP1-dependent cell death, mediated by the kinase RIPK3. Overall, the ability of ZBP1 to sense IAV infection signifies a point of divergence for IAV-induced programmed cell death pathways and inflammasome activation.
2016-08-11 | GSE77611 | GEO