Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dickkopf1 fuels inflammatory cytokine responses

ABSTRACT: Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1-controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3-restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and non-malignant cells and may be exploited therapeutically in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217231 | GEO | 2022/11/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dickkopf1 fuels inflammatory cytokine responses

Project description:Dickkopf1 fuels inflammatory cytokine responses

| PRJNA897934 | ENA

Thrombocytes-derived Dickkopf1 promotes wound-healing macrophage polarization

Project description:Immune responses are crucial to maintaining tissue homeostasis upon tissue injury. Upon various types of challenges, macrophages play a central role in regulating inflammation and tissue repair processes. While an immunomodulatory role of Wnt antagonist Dickkopf1 (DKK1) has been implicated, the role of Wnt antagonist DKK1 in regulating macrophage polarization in inflammation and the tissue repair process remains elusive. Here we found that DKK1 induces differential gene expression profiles from type 2-cytokine-activated macrophages to promote inflammation and tissue repair. Importantly, DKK1 induced pro-inflammatory and pro-resolving gene expressions via JNK (c-jun N-terminal kinase) in macrophages. Furthermore, DKK1 potentiated IL-13-mediated macrophage polarization and activation. Co-inhibition of JNK and STAT6 markedly decreased pro-inflammatory and pro-resolving gene expressions by DKK1 and IL-13. Interestingly, thrombocyte-specific deletion of DKK1 in mice reduced monocyte-derived macrophages in the acute sterile bleomycin (BLM)-induced lung injury model, suggesting that thrombocytes communicate with macrophages via DKK1 to orchestrate inflammation-induced injury repair process. Taken together, our study demonstrates DKK1’s role as a key regulatory role in macrophage polarization in the injury-induced inflammation and repair process.

2023-12-06 | GSE247398 | GEO

Gene Expression in the Liver after endotoxin

Project description:Acute Respiratory Distress Syndrome (ARDS) is a very common clinical entity and a major cause of morbidity and mortality in the critical care setting. Historically, ARDS has been associated with mortality ranging from 40% to 60% . In the US alone,200,000 new cases of ARDS occur every year. ARDS can be associated with different clinical disorders affecting the lungs. A novel ex-vivo swine model developed by our group permits measurements of lung pathophysiology and simultaneous collection of lung and liver tissue for histologic and molecular comparisons during the early phase of the response to endotoxemia. In this preparation, endotoxemia causes a liver-dependent inflammatory response and severe lung injury and dysfunction. We chose swine, as an experimental animal because, like humans, they are especially sensitive to endotoxin and the pathophysiology of the response appears to be similar to that in humans. Gene expression was evaluated in swine liver before and after endotoxin treatment.

2013-01-10 | E-MTAB-1436 | biostudies-arrayexpress

Mutant Huntingtin promotes neuronal death through cell autonomous microglial activation via myeloid lineage- determining factors

Project description:Huntington's Disease (HD) is a fatal neurodegenerative disorder caused by an extended polyglutamine repeat in the N-terminus of the huntingtin (Htt) protein. Reactive microglia and elevated cytokine levels are observed in the brains of HD patients, but the extent to which neuroinflammation results from extrinsic or cell-autonomous mechanisms is unknown. Furthermore, the impact of microglia activation on the pathogenesis of HD remains to be established. Using genome-wide approaches, we show that expression of mutant Htt in microglia promotes cell-autonomous pro-inflammatory transcriptional activation within microglia by increasing the expression and transcriptional activities of the myeloid lineage-determining factors PU.1 and C/EBPs. Elevated levels of PU.1 and its target genes are observed in the brains of mouse models and HD individuals. Moreover, mutant Htt expressing microglia exhibit an increased capacity to induce neuronal death ex vivo and in vivo in the presence of sterile inflammation. These findings suggest that expression of mutant Htt in microglia may contribute to neuronal pathology in Huntingtin disease. RNA-Seq and ChIP-Seq for PU.1, C/EBP, and H3K4me2 in BV2 cells and RNA-Seq in primary microglia and macrophages

2014-03-02 | E-GEOD-54443 | biostudies-arrayexpress

Dickkopf 1 Impairs Sensitivity to PD-1 Blockade through CD8+ T Cell Inactivation in dMMR/MSI Colorectal Cancer

Project description:Dickkopf 1 (DKK1) could promote tumor progression by suppressing immunity. Therefore, we investigated whether DKK1 influence prognosis and sensitivity to PD-1 blockade in colorectal cancers (CRCs) with defective DNA mismatch repair genes (dMMR) or microsatellite instability (MSI). We found that elevated DKK1 expression was associated with recurrence and dismissed CD8+ T cell infiltrations, and patients with high serum DKK1 had poor anti-PD-1 response. RNA interference or neutralization of DKK1 in CRCs enhanced CD8+ T cell cytotoxicity, and down-regulation of T-bet and E2F1 following GSK3β activation was detected in DKK1-treated CD8+ T cells. In organoid-lymphocyte co-culture model, apoptosis proportions were elevated after individual neutralization of both PD-1 and DKK1, and the combined neutralization resulted in further increases. In conclusion, DKK1 suppresses tumor immunity in dMMR/MSI CRCs by inactivating CD8+ T cells through GSK3β/E2F1/T-bet axis. DKK1 neutralization may improve the sensitivity to PD-1 blockade in dMMR/MSI CRCs.

2021-04-07 | GSE149206 | GEO

Endothelial dysfunction in NR2F2-silenced cells - human coronary artery endothelial cells model

Project description:Orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor 2 (COUPTF2; NR2F2) is highly expressed in endothelial cells (ECs) and Nr2f2 knockout produces lethal cardiovascular defects. In humans, NR2F2 mutations result in both congenital heart disease and diaphragmatic hernia, conditions associated with the development of pulmonary arterial hypertension (PAH). However, COUPTF2 functions in mature endothelium are uncertain. NR2F2 knockdown in primary human endothelial cells (ECs) led to an interferon-biased inflammatory response, endothelial-to-mesenchymal transition, proliferation, hypermigration, apoptosis-resistance and mitochondrial dysfunction. These phenotypic changes were associated with AKT activation and increased Dickkopf-1 (DKK1) expression, a Wnt/β-catenin pathway inhibitor. DKK1 was also elevated in patients with PAH and secreted in response to loss of bone morphogenetic receptor type 2 (BMPR2), the archetypal PAH-associated genetic defect. Together, these findings demonstrate that endothelial NR2F2 suppresses inflammation and proliferation. Thus, NR2F2 loss disrupts EC homeostasis and may promote pathologic vascular remodeling in the development of PAH.

2023-05-31 | GSE188466 | GEO

Endothelial dysfunction in NR2F2-silenced cells - EA.hy926 cells model

2023-05-31 | GSE188465 | GEO

Endothelial dysfunction in NR2F2-silenced cells - human lung microvascular endothelial cells model

2023-05-31 | GSE188467 | GEO

Tissue-specific RNA-seq in human evoked inflammation identifies novel blood and adipose lincRNA signatures of cardio-metabolic diseases

Project description:Inappropriate or sustained activation of innate immunity is a pathologic feature of several common cardio-metabolic disorders. Little is known, however, about transcriptomic modulation during inflammatory stress in disease-relevant human tissues. We applied deep RNA sequencing (RNA-seq) during low-dose experimental endotoxemia (LPS) in healthy humans to interrogate, in an unbiased manner, inflammatory tissue-level transcriptome responses of relevance to complex cardio-metabolic diseases. We utilized adipose and blood samples from three individuals who underwent a standardized inpatient endotoxemia protocol. Our comprehensive analysis revealed substantial, highly tissue- and subject-specific LPS-modulated changes in the expression of protein-coding genes and linc-RNAs as well as alternative splicing (AS). We also confirmed adipocytes and macrophages as potential cell sources of selective LPS-modulated linc-RNAs and AS events. Finally, we defined disease relevance of a subset of findings in obese adipose tissue and through interrogation of overlap with genome-wide association study loci for cardio-metabolic traits. Our findings provide novel insights into tissue-level genomic regulation, not detectable through analysis of DNA variations alone, of relevance to common cardio-metabolic diseases. Using RNA-seq data to study LPS-modulated changes in lincRNA expression for adipose and blood of a healthy individual.

2014-01-02 | E-GEOD-50792 | biostudies-arrayexpress

RNA-seq of human peripheral blood mononuclear cells

Project description:Inflammatory cytokine responses to activation of innate immunity differ between individuals, yet the genomic and transcriptomic determinants of inflammatory responsiveness are not well understood. We hypothesized that mRNA and lincRNA expression is modulated in disease-relevant tissues in humans in vivo during inflammation, and differs between individuals with divergent evoked inflammatory responses. In the Genetics of Evoked Response to Niacin and Endotoxemia (GENE) Study, we performed an inpatient endotoxin challenge (1ng/kg LPS) in healthy humans. We selected individuals in the top (high-responders) and bottom (low-responders) extremes for inflammatory responses, and applied RNASeq to peripheral blood mononuclear cells (PBMC, n=15) before and after LPS administration. At baseline, there were limited differences in gene expression by sex or race. Further, only a small number of genes differed between high and low responders at baseline. Post-LPS, there were clear differences in the magnitude of the transcriptional response between high and low responders, with a far greater number of genes differentially expressed post-LPS in high responders, consistent with the clinical response. We also found a number of differentially expressed long intergenic non-coding RNAs (lincRNAs) post-LPS. We show that differences in gene expression may drive differences in clinical inflammatory response, and that differentially expressed genes and lincRNAs represent novel candidates for modulation of immune and metabolic responses in acute and chronic diseases.

2016-09-27 | GSE87290 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data