Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1069120 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27730051_1.fastq.gz | Fastqsanger.gz | |||
| SRR27730051_2.fastq.gz | Fastqsanger.gz | |||
| SRR27730052_1.fastq.gz | Fastqsanger.gz | |||
| SRR27730052_2.fastq.gz | Fastqsanger.gz | |||
| SRR27730053_1.fastq.gz | Fastqsanger.gz |
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Project description:<p><strong>BACKGROUND:</strong> Cryopyrin-Associated Periodic Syndrome (CAPS) is an autoinflammatory condition consequence of monoallelic variants in the NLRP3 gene that exacerbate IL-1β production. These variants are gain-of-function, but the exact regulatory mechanism of the NLRP3 CAPS-inflammasome is not well yet understood. It is considered as a hypersensitive inflammasome triggered by cell priming, but patients with CAPS and animal disease models present inflammatory flares in the absence of external triggers.</p><p><strong>OBJECTIVES:</strong> To study the regulation and activation of the NLRP3 inflammasome in CAPS.</p><p><strong>METHODS:</strong> CAPS derived blood samples and genetically modified macrophages expressing different NLRP3 CAPS-associated variants were used to assess NLRP3 function dissociated from cell priming and cell metabolism.</p><p><strong>RESULTS:</strong> We found that CAPS-associated variants constitutively result in active NLRP3 inflammasomes, that induce a basal cleavage of gasdermin D, IL-18 release and pyroptosis. The constitutive active NLRP3 inflammasome was blocked by MCC950 and was dependent on NLRP3 expression level, being further regulated by deubiquitination. We also showed that activation of NF-κB with lipopolysaccharide or other endogenous host-derived molecules (palmitate, S100A9 or IL-6) further modulated the activation of the NLRP3 CAPS inflammasome and expanded the repertoire of molecules secreted from CAPS macrophages to IL-1β, IL-1α, HMGB1, cystatin B and the P2X7 receptor, identifying novel proteins involved in CAPS pathogenesis. NLRP3 inflammasomes with CAPS associated variants affected the immunometabolism of the myeloid compartment and impaired glycolysis.</p><p><strong>CONCLUSIONS:</strong> These findings demonstrate that NLRP3 CAPS-associated variants form a constitutive active inflammasome that induce basal pyroptosis and IL-18 release without cell priming, suggesting a priming-independent mechanism for the initiation of CAPS flares characterized with a profound affection in the immunometabolism.</p>
2024-01-09 | MTBLS7872 | MetaboLights
Project description:Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. Previously, we engineered an IL-2 “superkine” (H9) with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retain high-affinity for IL-2Rβ, thereby inhibiting binding of endogenous IL-2, but their engagement of γc is weakened, thereby attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues act as partial agonists and can differentially affect lymphocytes poised at distinct activation thresholds. Moreover, one of these variants potently antagonized IL-2 and IL-15 signaling and function better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft versus host disease and blocked spontaneous proliferation of smoldering adult T-cell leukemia (ATL) T cells ex vivo. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation. Genome-wide transcription factors binding of STAT5 and mRNA-Sequencing of gene expression profiles in human pre-activated CD8+ T cells.
2015-06-16 | E-GEOD-64713 | 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.
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Project description:Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. Previously, we engineered an IL-2 “superkine” (H9) with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retain high-affinity for IL-2Rβ, thereby inhibiting binding of endogenous IL-2, but their engagement of γc is weakened, thereby attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues act as partial agonists and can differentially affect lymphocytes poised at distinct activation thresholds. Moreover, one of these variants potently antagonized IL-2 and IL-15 signaling and function better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft versus host disease and blocked spontaneous proliferation of smoldering adult T-cell leukemia (ATL) T cells ex vivo. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation.
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Project description:Adult-onset Still’s disease (AOSD) is systemic autoinflammatory disorder of unknown aetiology. Various genetic and environmental factors have been implicated in its pathogenies, but the genetic studies so far have been limited to few selected genes of interest. We conducted detailed genetic analysis of a large cohort of patients with AOSD, using deep whole exome sequencing to identify rare germline variants and somatic mutations of interest. In parallel, we conducted a comprehensive inflammatory marker profiling from the patients’ sera. We used a bespoke assay to detect NLRP3 inflammasome activation and novel method to measure Type I Interferon (IFN) score. We found a strong genetic connection between AOSD and the presence of rare germline variants and somatic mutations within genes associated with monogenic autoinflammatory disorders and clonal haematopoiesis of unknown significance. Profiling of inflammatory markers showed significantly elevated ASC/NLRP3 speck levels in AOSD compared to healthy controls, whilst cytokine analysis identified several significantly elevated cytokines including IL-18, IL-6, IL-23, IFN and IFN-2. The Type I IFN score was also significantly higher in AOSD compared to healthy and some disease controls. We did not find any correlation between rare genetic variants and somatic mutation burden with selected inflammatory markers (ASC/NLRP3 speck, ASC speck, IL-1IL-18, IL-6 and Type I IFN score). Our study demonstrated considerable genetic complexity within AOSD. Many enriched variants may not be sufficient, individually to cause disease but more likely to contribute to a multiple-hit model for AOSD.
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2020-01-27 | E-MTAB-7764 | biostudies-arrayexpress
Project description:While certain human genetic variants are conspicuously loss-of-function, decoding the functional impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies in Gata2 enhancer-mutant hematopoietic progenitor cells to reveal how the insertion impacts GATA2 function genome-wide. Despite being nuclear-localized, 9aa-Ins was severely defective, with activation more impaired than repression. Variation of the inter-zinc finger spacer length revealed that repression tolerated insertions that were detrimental to activation. GATA2 deficiency generated a hematopoiesis-disrupting signaling network in progenitor cells with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling causes bone marrow failure, hallmark phenotypes of GATA2-deficiency patients, these results establish molecular mechanisms underlying GATA2-linked pathologies.
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Project description:While certain human genetic variants are conspicuously loss-of-function, decoding the functional impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies in Gata2 enhancer-mutant hematopoietic progenitor cells to reveal how the insertion impacts GATA2 function genome-wide. Despite being nuclear-localized, 9aa-Ins was severely defective, with activation more impaired than repression. Variation of the inter-zinc finger spacer length revealed that repression tolerated insertions that were detrimental to activation. GATA2 deficiency generated a hematopoiesis-disrupting signaling network in progenitor cells with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling causes bone marrow failure, hallmark phenotypes of GATA2-deficiency patients, these results establish molecular mechanisms underlying GATA2-linked pathologies.
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