Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Purinergic Preconditioning Induces Epigenomic and Transcriptomic Changes Resembling Epilepsy-associated Microglial States

ABSTRACT: Microglia are the main immune effector cells in the central nervous system (CNS) and contribute to a wide spectrum of neuropathological conditions through exacerbated activation. Microglial inflammatory responses may be conditioned by prior exposures to noxious stimuli, such as increased levels of extracellular adenosine and ATP. These levels are characteristic of brain insults like epileptic seizures and could potentially determine subsequent responses through epigenetic regulation. In this study, we investigated DNA methylation and expression changes in microglia-like cells differentiated from monocytes following ATP-mediated preconditioning. First, during microglia differentiation, we mainly observed DNA demethylation in genomic sequences enriched in binding motifs of microglia lineage transcription factors like PU.1, consistent with the relevance of this factor in in vivo microglia. TLR-mediated activation, after a first exposure to ATP, promoted exacerbated pro-inflammatory activation in comparison to cells not pre-exposed to ATP. These changes were accompanied by DNA methylation and transcriptional reprogramming of immune-related pathways, neurotransmitter activity and nucleotide phosphorylation. Finally, the epigenetic and transcriptional reprogramming associated with ATP-mediated preconditioning results in profiles found in microglia subsets linked to epilepsy. Purine-driven microglia immune pre-conditioning associates with epigenetic and transcriptional changes that might contribute to altered functions of microglia during seizure development and progression, particularly associated with neuroinflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272030 | GEO | 2024/07/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Purinergic Preconditioning Induces Epigenomic and Transcriptomic Changes Resembling Epilepsy-associated Microglial States

Project description:DNA methylation profiling of monocytes and monocyte-derived microglia like cells. Innate immune memory was explored in microglia-like cells through consecutive exposure to ATP and LPS.The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs.

2024-07-09 | GSE235104 | GEO

Negative feedback control of neuronal activity by microglia

Project description:Microglia, the brain resident macrophages, play a key role in the regulation of brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. We have identified a new function of microglia as critical modulators of neuronal activity and associated behavioral responses in mice. We show that microglia respond to neuronal activation and that ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. The suppressive impact of microglia on neuronal activation occurs in a highly localized fashion and depends on the ability of microglia to sense and catabolize extracellular ATP. ATP, which can be released upon neuronal activation by neurons and astrocytes, triggers the recruitment of microglia protrusions and is converted by the microglial ATP-hydrolyzing enzyme CD39 and CD73 into AMP and adenosine, a potent suppressor of neuronal activity. We show that the microglial sensing of ATP, the ensuing production of adenosine, and the adenosine-mediated control of neuronal response via the A1R are essential for the microglia-mediated regulation of neuronal activity and animal behavior. Our findings suggest that this microglia-driven negative feedback mechanism operates in a fashion similar to inhibitory neurons and plays an essential role in protecting the brain from excessive activation in health and diseases.

2020-08-18 | GSE149897 | GEO

Purinergic Preconditioning Induces Epigenomic and Transcriptomic Changes Resembling Epilepsy-associated Microglial States

Project description:Purinergic Preconditioning Induces Epigenomic and Transcriptomic Changes Resembling Epilepsy-associated Microglial States

| PRJNA984338 | ENA

Purinergic Preconditioning Induces Epigenomic and Transcriptomic Changes Resembling Epilepsy-associated Microglial States

Project description:Purinergic Preconditioning Induces Epigenomic and Transcriptomic Changes Resembling Epilepsy-associated Microglial States

| PRJNA1134737 | ENA

Cannabinoid receptor 2 is necessary to induce toll-like receptor-mediated microglial activation.

Project description:The tight regulation of microglia activity is key for precise responses to potential threats, while uncontrolled and exacerbated microglial activity is neurotoxic. Microglial toll-like receptors (TLRs) are indispensable for sensing different types of assaults and triggering an innate immune response. Cannabinoid receptor 2 (CB2) signaling is a key pathway to control microglial homeostasis and activation, and its activation is connected to changes in microglial activity. We aimed to investigate how CB2 signaling impacts TLR-mediated microglial activation. Here, we demonstrate that deletion of CB2 causes a dampened transcriptional response to prototypic TLR ligands in microglia. Loss of CB2 results in distinct microglial gene expression profiles, morphology, and activation. We show that the CB2-mediated attenuation of TLR-induced microglial activation is p38 MAPK-dependent. Taken together, we demonstrate that CB2 expression and signaling are necessary to fine-tune TLR-induced activation programs in microglia.

2021-08-23 | GSE173337 | GEO

Proteomic alterations in microglia with ischemic stroke and effect of LPS treatment

Project description:Ischemic stroke is a common acute CNS disorder leading to nearly half a million deaths per year in Europe. The high mortality is primarily owed to the limited treatment options of restoring blood flow in a narrow time window of several hours. Furthermore, inflammatory processes in the days and weeks after ischemic stroke contribute to tissue loss and neurological deficits. The key cells that influence and control this inflammatory cascade are microglia, the innate immune cells of the CNS. Microglia can be influenced and activated by e.g. lipopolysaccharide (LPS),a bacterial cell membrane component. It has been previously shown, that repetitive LPS stimuli prior to infarction (termed immunological preconditioning) lead to reduced infarct volumina in mouse models of ischemic stroke. Furthermore, our laboratory has shown, that phosphoinositide-3 kinase gamma mediates microglial functions after LPS-preconditioning. Hence, the aim of this work was to characterize proteomic alterations in microglia with (I) ischemic stroke in general in the tMCAO (transient middle cerebral artery occlusion) mouse model of ischemic stroke, (II) the influence of LPS-preconditioning on microglial proteomic alterations after tMCAO and (III) the role of PI3Ky in the microglial proteomic changes after tMCAO and preconditioning. This was done by a single LPS injection 3 days before tMCAO in wildtype mice and mice with PI3Ky knockout or knockin of the kinase dead form of PI3Ky.

2024-03-22 | PXD031930 | Pride

SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta

Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1Î² selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1Î² transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1Î². Consistent with our findings in mice, selective hypomethylation of IL-1Î² at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia

2014-10-01 | E-GEOD-56452 | biostudies-arrayexpress

Microglia in ischemic brain injury

Project description:Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene expression and phenotypic profile of a variety of endogenous CNS cell types (astrocytes, neurons, microglia) as well as an influx of leukocytic cells (neutrophils, macrophages, T-cells) from the periphery. Many molecules and conditions can trigger a transformation of ârestingâ (or surveying) microglia to an âactivatedâ (alerted/reactive) state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. Emphasis is placed on the role of specific molecular signaling systems such as hypoxia inducible factor-1 (HIF-1) and toll-like receptor-4 (TLR4) in regulating the microglial response in this setting. We then review histological and recent novel radiological data that confirms a key role for microglial activation in the setting of ischemic stroke in humans. We discuss recent progress in the pharmacological and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in preemptively targeting microglial activation in order to reduce stroke severity. 12 arrays, 4 experimental groups, 3 replicates in each group, CN is control normoxia, CH is control hypoxia, TN is TLR4 knockout normoxia, TH is TLR4 knockout hypoxia.

2010-10-05 | E-GEOD-18602 | biostudies-arrayexpress

ATP MODIFIES THE PROTEOME OF EXTRACELLULAR VESICLES RELEASED BY MICROGLIA AND INFLUENCES THEIR ACTION ON ASTROCYTES

Project description:Extracellular ATP is among molecules promoting microglia activation and inducing the release of extracellular vesicles (EVs), which are potent mediators of intercellular communication between microglia and the microenvironment. We previously showed that EVs produced under ATP stimulation (ATP-EVs) propagate a robust inflammatory reaction among astrocytes and microglia in vitro and in mice with subclinical neuroinflammation. However, the proteome of EVs released upon ATP stimulation has not yet been elucidated. In this study we applied a label free proteomic approach to characterize the proteome of EVs released constitutively and during microglia activation with ATP. We show that ATP drives sorting in EVs of a set of proteins implicated in cell adhesion/extracellular matrix organization, autophagy-lysosomal pathway and cellular metabolism, that may influence the response of recipient astrocytes to EVs. These data provide new clues to molecular mechanisms involved in microglia response to ATP and in microglia signalling to the environment via EVs.

2018-10-24 | PXD007650 | Pride

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [snRNA-Seq]

Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.

2022-03-10 | GSE198014 | 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