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Detailed genotype-phenotype analysis of AOSD cohorts

ABSTRACT: 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-1IL-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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244372 | GEO | 2025/05/07

REPOSITORIES: GEO

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Project description:BACKGROUND: 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.OBJECTIVES: To study the regulation and activation of the NLRP3 inflammasome in CAPS.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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.

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.

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Detailed genotype-phenotype analysis of AOSD cohorts

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