Hypoxia-induced priming of microglial inflammatory gene expression is associated with TLR4 signaling H3K4me3 enrichment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE108770 | GEO | 2020/02/04
REPOSITORIES: GEO
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Project description:Hypoxia-induced priming of microglial inflammatory gene expression is associated with TLR4 signaling H3K4me3 enrichment
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Project description:Hypoxia (Hx) is a component of multiple disorders, including stroke and sleep-disordered breathing, which often precede or are comorbid with neurodegenerative diseases. However, little is known about how hypoxia affects the ability of microglia, resident CNS macrophages, to respond to subsequent inflammatory challenges that are often present during neurodegenerative processes. We, therefore, tested the hypothesis that hypoxia would enhance or "prime" microglial pro-inflammatory gene expression in response to a later inflammatory challenge without programmatically increasing basal levels of pro-inflammatory cytokine expression. To test this, we pre-exposed immortalized N9 and primary microglia to hypoxia (1% O2) for 16 h and then challenged them with pro-inflammatory lipopolysaccharide (LPS) either immediately or 3-6 days following hypoxic exposure. We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to analyze primed microglial inflammatory gene expression and modifications to histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of primed genes. We found that microglia exhibited enhanced responses to LPS 3 days and 6 days post-hypoxia. Surprisingly, however, the majority of primed genes were not enriched for H3K4me3 acutely following hypoxia exposure. Using the bioinformatics tool MAGICTRICKS and reversible pharmacological inhibition, we found that primed genes required the transcriptional activities of NF-κB. These findings provide evidence that hypoxia pre-exposure could lead to persistent and aberrant inflammatory responses in the context of CNS disorders.
| S-EPMC7575929 | biostudies-literature
Project description:Primary microglial cultures from neonatal mice were exposed to hypoxia (1% O2, 6 h) and their global gene expression profile was analyzed. This data were used to described the Hypoxic Microglia Signature, genes that were up- or down-regulated by hypoxia in microglial cells in culture.
2021-03-08 | GSE97423 | GEO
Project description:We analyzed gene expression via RNA-sequencing in microglia isolated from postnatal day 9 rats exposed to normoxia or intermittent hypoxia, in the presence or absence of lipopolysaccharide
2019-07-12 | GSE126946 | GEO
Project description:The only validated treatment to prevent brain damage associated with hypoxia-ischemia (HI) encephalopathy of the newborn is controlled hypothermia with limited benefits. Additional putative neuroprotective drug candidates include sildenafil citrate, a phosphodiesterase-type 5 inhibitor. The main objective of this preclinical study is to assess its ability to reduce HI-induced neuroinflammation, in particular through its potential effect on microglial activation. HI was induced in P10 Sprague–Dawley rats by unilateral carotid permanent artery occlusion and hypoxia (HI), and treated by either hypothermia (HT) alone, Sildenafil (Sild) alone or combined treatment (SildHT). Lesion size, glial activation were analyzed by immunohistochemistry, qRT-PCR and proteomic analyses performed at P13. Exposure to any treatment was not associated with significant reduction in lesions size both in cerebral cortex and hippocampus, 72h after HI. Significant reductions in either Iba1+ (within the ipsilateral hemisphere) or GFAP+ cells (within the ipsilateral hippocampus) were observed in SildHT group, but not in the other treatment groups. In microglia sorted cells, pro-inflammatory markers, ie. Il1b, Il6, Nos2, and CD86 were significantly downregulated in SildHT treatment group only. These changes were restricted to ipsilateral hemisphere, were not evidenced in sorted astrocytes, and were not sex-dependent. Proteomic analyses in sorted microglia refined the pro-inflammatory effect of HI and confirmed a biologically relevant impact of SildHT on specific molecular pathways including notably genes related to neutrophilic functions. Our findings demonstrate that Sildenafil combined with controlled hypothermia confers maximum effect to mitigate microglial activation induced by HI through complex proteomic regulation. The reduction of neuroinflammation induced by Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.
2024-04-30 | PXD045168 | Pride
Project description:Effects of treatment with Nimodipine on N9 cells
2017-04-11 | GSE87397 | GEO
Project description:Purpose: Recent findings indicate a regulatory role of microglia on neurogenesis in the SVZ in health and disease. Microglia in the early postnatal SVZ are not fully maturated and may react differently than adult microglia to injury. We sought to investigate the impact of cortico-striatal neonatal HI injury on the microglial phenotype in the early postnatal SVZ. Results: In comparison to sham SVZ microglia, HI SVZ microglia upregulate both pro- and anti-inflammatory genes as well as neurotrophic genes. HI SVZ microglia do not adopt a M1 or M2 polarization state, but instead share commonly expressed genes with microglia in rodent models of neurodegenerative diseases.
2020-01-13 | GSE97299 | GEO
Project description:Microglia are macrophages-like cells in the central nervous system (CNS) harboring important roles such as synaptic organization, phagocytosis of debris and apoptotic cells, and repairing damaged tissue. Microglial function is tightly controlled, but under certain pathological conditions, activated microglia can induce excess inflammation which injure live cells in the CNS. Therefore, suppression of microglia is a fundamental strategy to treat CNS disorders. We have previously shown that the antiepileptic drug levetiracetam (LEV) inhibits microglia activation, but mechanism remains unclear. The purpose of this study is to identify a target of LEV to suppress microglial activity.
2021-07-28 | GSE180828 | GEO
Project description:Microglial activation and sustained inflammation in the brain can lead to neuronal damage. Hence, limiting microglial activation and brain inflammation is a good therapeutic strategy for inflammatory-associated central nervous disease. MiR-146a is a promising therapeutic microRNA, since it can negatively regulate the inflammatory response. We thus investigated the expression changes of miR-146a after experimental induction of a subarachnoid hemorrhage (SAH) in vivo and in vitro, and we assessed the anti-inflammatory effects of miR-146a in microglial cells in vitro. Primary microglial cells were preincubated with miR-146a before hemoglobin (Hb) treatment. The results indicated that miR-146a decreased gene expression of Hb-induced pro-inflammatory cytokines (TNF-? and IL-1?) and phenotype-related genes (iNOS and CD86) through IRAK1/TRAF6/NF-?B or MAPK signaling pathways, suggesting its pro-resolution activity in microglia. However, contrary to the LPS-induced microglia or macrophage activation model, we did not observe an elevation in miR-146a after activation. Overall, our findings demonstrated that miR-146a was involved in the regulation of brain inflammation and could be considered a novel therapeutic agent for treating brain inflammation.
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Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
2015-07-06 | E-GEOD-70475 | biostudies-arrayexpress