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Arresting the Bad Seed: HDAC3 Regulates Proliferation of Different Microglia after Ischemic Stroke [RNA-seq]

ABSTRACT: The rapid accumulation of self-renewed polarized microglia in the penumbra is the critical neuroinflammatory process after the onset of ischemic stroke, leading to secondary demyelination and neuronal loss. HDAC3 has been reported to regulate cell proliferation of tumour cells and modulate neuroinflammation. However, the mechanism by which HDAC3 regulates microgliosis and microglial polarization remains ambiguous. Herein, we demonstrated that microglia-specific ablation of HDAC3 (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. Starting with unbiased RNA seq of microglia, we identified mitosis as the most significant process reversed by loss of HDAC3. Notably, HDAC3-miKO specifically inhibited the proliferation of M1-like microglia but not M2-like microglia, resulting in microglial transition to an M1-like state. Moreover, ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) revealed that HDAC3 deletion induced drastic closing of accessible regions enriched with motifs for PU.1. Taken together, we uncovered for the first time that HDAC3/PU.1-mediated differential proliferation-related reprogramming in different microglia populations drives poststroke inflammatory state transition of microglia and thereby contributes to the pathophysiology of ischemic stroke.

ORGANISM(S): Mus musculus

PROVIDER: GSE220042 | GEO | 2024/03/13

REPOSITORIES: GEO

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Arresting the Bad Seed: HDAC3 Regulates Proliferation of Different Microglia after Ischemic Stroke [ATAC-seq]

Project description:The rapid accumulation of self-renewed polarized microglia in the penumbra is the critical neuroinflammatory process after the onset of ischemic stroke, leading to secondary demyelination and neuronal loss. HDAC3 has been reported to regulate cell proliferation of tumour cells and modulate neuroinflammation. However, the mechanism by which HDAC3 regulates microgliosis and microglial polarization remains ambiguous. Herein, we demonstrated that microglia-specific ablation of HDAC3 (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. Starting with unbiased RNA seq of microglia, we identified mitosis as the most significant process reversed by loss of HDAC3. Notably, HDAC3-miKO specifically inhibited the proliferation of M1-like microglia but not M2-like microglia, resulting in microglial transition to an M1-like state. Moreover, ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) revealed that HDAC3 deletion induced drastic closing of accessible regions enriched with motifs for PU.1. Taken together, we uncovered for the first time that HDAC3/PU.1-mediated differential proliferation-related reprogramming in different microglia populations drives poststroke inflammatory state transition of microglia and thereby contributes to the pathophysiology of ischemic stroke.

2024-03-13 | GSE220041 | GEO

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

Next Generation Sequencing Facilitates Quantitative Analysis of Poststroke Anxiety and General Anxiety Transcriptomes and Predictive Description of Downstream Transcriptional Differences with HDAC3 Inhibitor Treatment or not.

Project description:Our study represents the first detailed analysis of transcriptomes between poststroke anxiety and General Anxiety by RNA-seq technology. We founded that: compared with pure restraint stress, stroke plus restraint stress leaded to other pathways: 1) Oxidative stress and redox pathways are out-of-balance; 2). Production of nitric oxide is disordered; 3). Mitochondrial ATP synthesis is coupled with electron transport pathway dysfunction. These upregulated genes analyzed integrally were greatly enriched in the regulation of cytokine production, inflammatory response and leukocyte infiltration. And our results detailly predicted downstream transcriptional differences with HDAC3 inhibitor treatment or not in poststroke anxiety. We concluded that HDAC3-regulated PGE2 production by microglia constitutes phobic anxiety susceptibility after stroke.

2022-01-28 | GSE194326 | 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

High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Protects Against Ischemic Stroke by Inhibiting M1 Microglia Polarization through Let-7b-5p/HMGA2/NF-κB Signaling Pathway

Project description:Modulating M1/M2 polarization is a potential therapy for treating ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) held the capacity to regulate astrocytic polarization, but little is known about rTMS effects on microglia. Therefore, the present study aimed to investigate whether and how rTMS influence microglia polarization in ischemic stroke models. The 10-Hz rTMS was applied to transient middle cerebral artery occlusion (MCAO) rats and oxygen and glucose deprivation/ reoxygenation injured BV2 cells. Western blot, immunofluorescence and ELISA were used to detect M1/M2 markers. High-throughput sequencing, RT-PCR and FISH staining were adopted to test microRNA changes. The 10-Hz rTMS inhibited ischemia/reperfusion induced M1 microglia and significantly increased let-7b-5p. HMGA2 was proved to be the target protein of let-7b-5p and its downstream NF-κB signaling pathway were inhibited by rTMS. Microglia culture medium (MCM) collected from rTMS treated microglia had low TNF-α but high IL-10 concentration, leading to reduced neural death, minor ischemic volumes and improved functional recovery of MCAO animals. However, knockdown of let-7b-5p by antagomir reversed rTMS effects on microglia. In conclusion, high-frequency rTMS could improve functional recovery through inhibiting M1 microglia polarization via regulating let-7b-5p/HMGA2/NF-κB signaling pathway in cerebral ischemic stroke models.

2022-08-10 | GSE192910 | GEO

The role of microglial lnc-U90926 in ischemic stroke

Project description:Dysregulated long non-coding RNAs (lncRNAs) have been shown to contribute to the pathogenesis of ischemic stroke. However, the potential role of lncRNAs in post-stroke microglial reactivation remains largely unknown. Here, we uncovered that lncRNA-U90926 was significantly increased in the microglia exposed to ischemia/reperfusion in vivo and in vitro. In addition, adenovirus associated virus (AAV)-mediated microglial U90926 silencing alleviated neurological deficits and reduced infarct volume in experimental stroke mice. Microglial U90926 knockdown could reduce the infiltration of neutrophils into ischemic lesion site, which might be attributed to the downregulation of C-X-C motif ligand 2 (CXCL2). Mechanistically, U90926 directly bound to malate dehydrogenase (MDH2) and competitively inhibited MDH2-mediated decay of CXCL2 mRNA. Taken together, our study demonstrated that microglial U90926 aggravated ischemic brain injury via facilitating neutrophil infiltration, suggesting that U90926 might be a potential biomarker and therapeutic target for ischemic stroke.

2020-10-24 | GSE159903 | GEO

Microglia transcriptome in a rat model of ischemic stroke

Project description:Microglia are key regulators of inflammatory response after stroke and brain injury. Here we profiled the microglia transcriptome isolated from a spontaneously hypertensive rat model of focal cerebral ischemia. We identified an extensive and persistent upregulation of anti-inflammatory M2-like patterns after stroke and a mild up-regulation of pro-inflammatory M1-like patterns at later stage. We also found that younger brains showed larger microglial response than middle aged brains. Moreover, beyond the standard M1/M2 dichotomy, a wide spectrum of novel microglial polarization states was activated in response to stroke, particularly the phenotypes related to Tlr2 and dietary fatty acids stimulation.

2020-04-24 | GSE148350 | GEO

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 “resting” (or surveying) microglia to an “activated” (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.

2010-10-05 | GSE18602 | GEO

Dynamic microglial gene expression profiles after ischemic stroke

Project description:Analysis of microglial gene expression profiles after ischemic stroke. Stroke is a complicated disease caused by the interaction of multiple celltypes. Results provide new insights into the molecular mechanisms underlying microglial activation after ischemic stroke.

2022-01-01 | GSE172456 | GEO

Gene expression profiles in microglia with or without PGC-1α overexpression

Project description:PGC-1α overexpression in microglia protects against ischemia-induced brain damage in mice. To investigate the underlying mechanism of PGC-1α, we have employed whole mRNA microarray expression profiling as a discovery platform to identify genes with the potential to change the microglial function. Indeed, PGC-1α overexpression alters the gene expression profiles of microglia, this suggested that microglial PGC-1α might play an important role after ischemic stroke.

2019-01-10 | GSE124874 | GEO

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