VEXAS syndrome is characterized by blood and tissues inflammasome pathway activation and monocyte dysregulation
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ABSTRACT:
PROVIDER: PRJNA894197 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22035268.fastq.gz | Fastqsanger.gz | |||
| SRR22035269.fastq.gz | Fastqsanger.gz | |||
| SRR22035270.fastq.gz | Fastqsanger.gz | |||
| SRR22035271.fastq.gz | Fastqsanger.gz | |||
| SRR22035272.fastq.gz | Fastqsanger.gz |
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Project description:Acquired mutations in the UBA1 gene, occurring in myeloid cells and resulting in expression of a catalytically impaired isoform of the enzyme E1, were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). The precise physiological and clinical impact of these mutations remains poorly defined. Here, we studied a unique prospective cohort of individuals with severe autoinflammatory disease with (VEXAS) or without (VEXAS-like) UBA1 somatic mutations and compared with low-risk myelodysplastic syndromes (MDS) and aged gender-matched healthy controls. We performed an integrated immune analysis including multiparameter phenotyping of peripheral blood leukocytes, cytokines profiling, bulk and single-cell gene expression analyses and skin tissue imaging mass cytometry. Focusing on myeloid cells, we show that monocytes from UBA1-mutated individuals were quantitatively and qualitatively impaired and displayed features of exhaustion with aberrant expression of chemokine receptors. Within affected tissues, pathological skin biopsies from VEXAS patients showed an abundant enrichment of CD16 + CD163 + monocytes adjacent to blood vessels and M1 macrophages, possibly promoting local inflammation in part through STAT3 activation. In peripheral blood from VEXAS patients, we identified a significant increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirmed the role of circulating cells in the IL-1β and IL-18 dysregulation in VEXAS patients and revealed a significant enrichment of TNF-a and NFkB signaling pathways that could mediate cell death and inflammation. Single-cell analysis confirmed the inflammatory state of monocytes from VEXAS patients and allowed us to identify specific molecular pathways that could explain monocytopenia, especially the activation of PANoptosis and a deficiency in the TYROBP/DAP12 axis and β-catenin signaling pathway. Together, these findings on monocytes from patients with UBA1 mutations provide important insights into the molecular mechanisms involving the mature myeloid commitment in VEXAS syndrome and suggest that the control of the undescribed inflammasome activation and PANoptosis could be novel therapeutic targets in this condition.
2023-11-06 | GSE216548 | GEO
Project description:Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.
| S-EPMC10828464 | biostudies-literature
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:Background and methods: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has been recently recognized as an adult-onset autoinflammatory syndrome due to somatic mutations affecting Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) gene. Following-up studies have been mostly limited to case reports; transcriptome of especially hematopoiesis in VEXAS syndrome has not been well characterized. Results: We performed whole transcriptome sequencing of single bone marrow cells (BMMNCs) and enriched Lineage-CD34+ hematopoietic stem and progenitor cells (HSPCs) from nine patients included in the original VEXAS cohort. We profiled inflammation and hematopoietic differentiation in these patients, and found activation of inflammatory gene programs particularly in marrow myeloid cells; HSPCs showed a preferred myeloid dominance. Patients had profound abnormalities in gene expression involved in pathways of inflammation, cell cycling and activation, and protein synthesis. We defined single bone marrow cells with expressed UBA1 mutations, and characterized gene expression of mutant myeloid cells as compared to that of wild-type, and observed upregulation of inflammatory pathways and immune activation; increased cell cycling might contribute to clonal dominance of UBA1 mutant cells. We were also able to profile other somatic mutations (DNMT3A) in two patients who had concurrent DNMT3A mutations at a high frequency. With coupled single cell T/B-cell receptor (TCR/BCR) sequencing, we characterized TCR and BCR repertoire in four patients, two of whom had B cell lymphocytosis. Cell-cell interaction analysis revealed enhanced interactions of myeloid cells with HSPCs, and interferons interaction with their receptors were frequent. We also performed bulk RNA sequencing of several leukemic cell lines with UBA1 knockdown, and observed upregulation of inflammatory pathways in these UBA1 knockdown cell lines. Conclusion: Our study discloses transcriptome signatures of hematopoietic cells in VEXAS syndrome, providing a broad perspective into potential pathogenesis of this novel disease.
2023-07-18 | GSE196052 | GEO
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.
2014-07-01 | GSE58959 | GEO
Project description:Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common non-malignant disorders. VEXAS syndrome is a recently discovered adult-onset autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms fueling clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. Here, we performed immunophenotypic dissection of hematopoiesis and single-cell transcriptomics in a VEXAS patient cohort revealing pervasive inflammation across all lineages. Hematopoietic stem/progenitor cells (HSPCs) in VEXAS patients proliferate less, are mostly committed toward myelopoiesis, and prone to egress from the bone marrow. Humanized xenograft models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, fully recapitulated patients’ hematologic and inflammatory hallmarks. Competitive transplants of VEXAS-like and normal HSPCs showed that while mutant cells are resilient to the inflammatory milieu, wild-type ones are poisoned and progressively overwhelmed by VEXAS clones, becoming unable to support functional multilineage hematopoiesis. Our study unveils an unanticipated mechanism of clonal dominance, provides new models for preclinical investigation of therapeutic strategies, and has relevant implications for clinical management of VEXAS patients.
2025-02-06 | GSE272816 | GEO
Project description:Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common non-malignant disorders. VEXAS syndrome is a recently discovered adult-onset autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms fueling clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. Here, we performed immunophenotypic dissection of hematopoiesis and single-cell transcriptomics in a VEXAS patient cohort revealing pervasive inflammation across all lineages. Hematopoietic stem/progenitor cells (HSPCs) in VEXAS patients proliferate less, are mostly committed toward myelopoiesis, and prone to egress from the bone marrow. Humanized xenograft models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, fully recapitulated patients’ hematologic and inflammatory hallmarks. Competitive transplants of VEXAS-like and normal HSPCs showed that while mutant cells are resilient to the inflammatory milieu, wild-type ones are poisoned and progressively overwhelmed by VEXAS clones, becoming unable to support functional multilineage hematopoiesis. Our study unveils an unanticipated mechanism of clonal dominance, provides new models for preclinical investigation of therapeutic strategies, and has relevant implications for clinical management of VEXAS patients.
2025-02-06 | GSE272578 | GEO
Project description:Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression and emergency hematopoiesis. Epigenetic changes, notably via histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes implicated in immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8). Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. These changes are recapitulated in septic mice following cecal slurry injection, supporting the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.
2024-03-05 | GSE242816 | GEO
Project description:UBA1 is an E1 enzyme essential for initiating ubiquitylation. We have identified 25 patients with somatic mutations in UBA1 that alter protein isoform expression in myeloid cells. We studied the transcriptional profiles of whole blood, and sorted cell populations from VEXAS patients.
2020-10-29 | GSE160268 | GEO
Project description:Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression and emergency hematopoiesis. Epigenetic changes, notably via histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes implicated in immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8). Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. These changes are recapitulated in septic mice following cecal slurry injection, supporting the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.
2024-03-05 | GSE253201 | GEO