Pluripotent stem cell model of Nakajo-Nishimura syndrome untangles proinflammatory pathways mediated by oxidative stress
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ABSTRACT:
PROVIDER: PRJNA438520 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6844880.fastq.gz | Fastqsanger.gz | |||
| SRR6844881.fastq.gz | Fastqsanger.gz | |||
| SRR6844882.fastq.gz | Fastqsanger.gz | |||
| SRR6844883.fastq.gz | Fastqsanger.gz | |||
| SRR6844884.fastq.gz | Fastqsanger.gz |
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Project description:Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction of the immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokines in NNS, the underlying mechanisms of the autoinflammation are still largely unknown. To investigate and understand the mechanisms and signal pathways in NNS, we established a panel of isogenic pluripotent stem cell (PSC) lines with PSMB8 mutation. Activity of the immunoproteasome in PSMB8-mutant PSC-derived myeloid cell lines (MT-MLs) was reduced even without stimulation compared to non-mutant-MLs. Additionally, MT-MLs showed an overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS) and phosphorylated p38 MAPK levels. Treatment with p38 MAPK inhibitor and anti-oxidants decreased the abnormal production of cytokines and chemokines. The current PSC model revealed a specific ROS-mediated inflammatory pathway, providing a platform for the discovery of alternative therapeutic options for NNS and related immunoproteasome disorders.
2018-05-03 | GSE111908 | GEO
Project description:Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction of the immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokines in NNS, the underlying mechanisms of the autoinflammation are still largely unknown. To investigate and understand the mechanisms and signal pathways in NNS, we established a panel of isogenic pluripotent stem cell (PSC) lines with PSMB8 mutation. Activity of the immunoproteasome in PSMB8-mutant PSC-derived myeloid cell lines (MT-MLs) was reduced even without stimulation compared with non-mutant-MLs. In addition, MT-MLs showed an overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS) and phosphorylated p38 MAPK levels. Treatment with p38 MAPK inhibitor and antioxidants decreased the abnormal production of cytokines and chemokines. The current PSC model revealed a specific ROS-mediated inflammatory pathway, providing a platform for the discovery of alternative therapeutic options for NNS and related immunoproteasome disorders.
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Project description:Activation of Coagulation and Proinflammatory Pathways in Thrombosis with Thrombocytopenia Syndrome and Following COVID-19 Vaccination
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Project description:Thrombosis with thrombocytopenia syndrome (TTS) is an extremely rare but potentially serious adverse event following immunization with the adenovirus vector-based COVID-19 vaccines Ad26.COV2.S (Janssen / Johnson & Johnson) or ChAdOx1 (AstraZeneca). However, no cases of TTS have been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States, suggesting that anti-vector immunity may reduce TTS risk. Here we show robust stimulation of platelet activation and coagulation pathways and innate immune pathways in patients with TTS but only transient activation of these pathways following vaccination. We evaluated proteomic profiles in 2 patients with TTS and transcriptomic and proteomic profiles in 20 people following an initial dose and a booster dose of Ad26.COV2.S and in 14 people who received the mRNA vaccines BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induced transient activation of platelet activation and coagulation pathways and innate proinflammatory pathways that resolved by day 7. TTS patients showed enhanced and sustained upregulation of these pathways, whereas a second immunization with Ad26.COV2.S or a reduced initial dose of Ad26.COV2.S resulted in lower activation of these pathways. These data provide insight into TTS pathogenesis and suggest a potential strategy for reducing TTS risk by lowering the dose of Ad26.COV2.S.
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Project description:Antiphospholipid antibodies induce Proinflammatory and Procoagulant Pathways in Endothelial cells.
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Project description:Background: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in Nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome. Objectives: To elucidate the mechanisms of autoinflammation in Blau syndrome, we sought to clarify the relation between disease associated-mutant NOD2 and the inflammatory response in human samples. Methods: Blau syndrome-specific induced pluripotent stem cells (iPSCs) lines were established. To precisely evaluate the in vitro phenotype of iPSC-derived cells, the disease-associated NOD2 mutation of iPSCs was corrected using a CRISPR/Cas9 system. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the status of NF-κB pathway and proinflammatory cytokine secretion were investigated. Results: We focused on the signals that upregulate the expression of NOD2, especially IFN-γ signaling. IFN-γ treatment of NOD2-mutant macrophages induced ligand-independent NF-κB activation and proinflammatory cytokine production. IFN-γ treatment acted as a priming signal through the up-regulation of NOD2 protein and recruitment of NOD2 on the basement membrane. Conversely, the production of proinflammatory cytokines by MDP, a ligand of NOD2, was decreased in mutant macrophages. Conclusions: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of Blau syndrome patients.
2018-01-24 | GSE98454 | GEO
Project description:The goal of this study was to define molecular overlap between Down syndrome and Fragile X syndrome using human pluripotent stem cells (hPSCs) and in vitro derived glutamatergic neurons.
2022-08-05 | GSE144857 | GEO
Project description:Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating long-term multisystem disorder with a central and inexplicably persistent fatigue symptom that is unable to be relieved by rest. Energy metabolism and oxidative stress have been recent focal points of ME/CFS research and in this study we were able to elucidate metabolic pathways that were indicative of their dysfunction. Blood and urine samples were collected from 34 females with ME/CFS (34.9 ± 1.8 SE years old) and 25 non-ME/CFS female participants (33.0 ± 1.6 SE years old). All samples underwent metabolic profiling via 1D 1H Nuclear magnetic resonance spectroscopy and quantitated metabolites were assessed for significance. Blood glucose was elevated while blood lactate, urine pyruvate, and urine alanine were reduced indicating an inhibition of glycolysis that may potentially reduce the provision of adequate acetyl-CoA for the citric acid cycle. We propose that amino acids are being increasingly used to provide an adequate carbohydrate source for the citric acid cycle. We suggest that this is via glutamate forming 2-oxoglutarate through an enzyme that deaminates it and subsequently elevates blood aspartate. Dysfunctional energy metabolism appears to have impacted creatinine and its elevation in urine suggests that it may be used as an alternative for anaerobic ATP production within muscle. A decrease in blood hypoxanthine and an increase in urine allantoin further suggest the elevation of reactive oxygen species in ME/CFS patients. These findings bring new information to the research of energy metabolism, chronic immune activation and oxidative stress issues within ME/CFS.
2015-06-08 | MTBLS161 | MetaboLights
Project description:Objective: The molecular mechanisms underlying polycystic ovary syndrome (PCOS) pathogenesis were investigated using an integrative metaprogram analysis framework, with specific focus on oxidative stress-related pathways through combined single-cell and bulk RNA sequencing approaches. Methods: Three datasets were integrated: a single-cell RNA-seq dataset (GSE240688), a laboratory-generated bulk RNA-seq dataset, and a validation microarray dataset (GSE34526). Transcriptional programs in granulosa cells were identified by non-negative matrix factorization, while dysregulated genes were characterized by differential expression and weighted gene co-expression network analyses. An integrative multi-omics approach was employed to identify key regulatory genes at the intersection of these complementary analytical methods. Results: Ten distinct transcriptional metaprograms in granulosa cells were identified, with metaprogram 4 (MP4) significantly enriched in PCOS samples and associated with oxidative stress response pathways. 199 consistently dysregulated genes across independent patient cohorts were revealed by differential expression analysis. Through integrative analysis, glutathione peroxidase 3 (GPX3) was identified as the only gene present across all three analytical approaches. GPX3 was significantly upregulated in PCOS samples with robust discriminatory power (AUC>0.8) and was functionally associated with insulin signaling, glucose metabolism, and mitochondrial pathways, suggesting its role in connecting oxidative stress and metabolic dysfunction. Conclusions: Oxidative stress responses were revealed as central to PCOS pathophysiology by our comprehensive multi-omics approach, with GPX3 identified as a key regulatory node connecting metabolic and reproductive dysfunction. A molecular basis for the oxidative stress-mediated pathology in PCOS is established by these findings.
2025-04-05 | GSE293353 | GEO
Project description:We have generated iPSCs from monosomy X (Turner Syndrome), trisomy 8 (Warkany Syndrome 2), trisomy 13 (Patau Syndrome) and partial trisomy 11;22 (Emanuel Syndrome), using either skin fibroblasts from affected individuals or amniocytes from antenatal diagnostic tests. These cell lines stably maintain the karyotype of the donors and behave like embryonic stem cells (ESCs) in all tested assays. Turner Syndrome iPSCs were used for further studies including global gene expression analysis and tissue-specific directed differentiation. Multiple clones displayed lower levels of the pseudoautosomal genes ASMTL and PPP2R3B than the controls. Moreover, they could be transformed into neural-like, hepatocyte-like and heart-like cells but displayed insufficient up-regulation of the pseudoautosomal placental gene CSF2RA during embryoid body (EB) formation. These data support that abnormal organogenesis and early lethality in Turner Syndrome are not caused by a tissue-specific differentiation blockade but rather involves other abnormalities including impaired placentation. Global gene expression profiling with DNA microarrays showed that 3 TS iPSC clones corresponding to the same patient showed a global gene expression pattern similar to ESCs and euploid iPSCs, and very different from donor cells .We detected transcriptomic changes between TS iPSCs and the other ESCs/iPSCs but these variations did not follow a pattern and in fact all pluripotent cell lines clustered together. For DNA microarray analysis, all cells were treated with Trizol, followed by RNA extraction and hybridization.
2011-10-03 | E-GEOD-32527 | biostudies-arrayexpress