Transcriptional Response of Human Microglial Cells to Interferon-gamma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE1432 | GEO | 2004/12/25
SECONDARY ACCESSION(S): PRJNA89967
REPOSITORIES: GEO
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Project description:Microglial cells are resident macrophages in the central nervous system (CNS) and play a pivotal role in the innate and adaptive immune responses against microbial infections. The immune functions of microglia are regulated by a milieu of cytokines including interferon (IFN)-gamma. We here performed a series of experiments to acertain the transcriptional profile of human fetal microglial cells at 1, 6, and 24 h after IFN-gamma treatment. Primary human microglial cells were either untreated or treated with 200u/ml IFN-gamma. Affymetrix U133A chips were utilized. Four different tissue samples (B18, O, W, and Y20) were analyzed at the three time points.
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Project description:IFN-gamma is a classical microglial stimulant. We used microarrays to investigate the microglial gene regulatory network activated by interferon-gamma. Experiment Overall Design: Primary rat microglia cultures were established and maintained for 15 days. For activation studies, fresh media containing IFN-gamma (100 U/ml) were added and left overnight (16 hours). Total RNA was extraction and hybridized on Affymetrix microarrays (RG_U34A). Five arrays were run from total RNA derived from unstimulated 5 independent cultures (Mgl_CON1, Mgl_CON2, Mgl_CON3, Mgl_CON5 and Mgl_CON6). Three standard microglial cultures were stimulated (Mgl_IFNgamma_2 and Mgl_IFNgamma_3) with one of the samples analysed in triplicate as a technical control (Mgl_IFNgamma_1a, Mgl_IFNgamma_1b and Mgl_IFNgamma_1c).
2008-06-14 | E-GEOD-6353 | biostudies-arrayexpress
Project description:Microglia become activated by disturbances in the homeostasis of their local microenvironment. While there are varying degrees of microglia activation, a pro-inflammatory reactive state induced by exposure to stimuli like LPS and IFN-γ. In this study, we identified a total of 5497 proteins in whole cell proteome and 4938 proteins for secretome of activated BV-2 mouse microglia cell line with LPS or IFN-γ using improved shotgun proteomic approach. From the differentially expressed proteins in stimulated microglia, we were able to classify pathways related immune-inflammatory response or metabolism. Moreover, we performed longitudinal quantification of secreted proteins during the detrimental activation of microglia which releases neurotoxic molecules mediated neuronal cell loss in the brain region.
2017-08-09 | PXD006558 | Pride
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Primary microglia (WT, USP18ko and USP18_C61A mice) and BV-2 cells (treated with control siRNA or siRNA against USP18) were incubated with 500 U/ml IFN-b. At different timepoints (0h, 6h, and 24h) RNA samples were taken and analyzed via Microarray
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Project description:Cx3cr1CreER driven Cre-recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia and macrophages. However, an in-depth analysis for the possible detrimental effects of Cre-activity in microglia, surprisingly remains missing. Here we demonstrate an age-dependent sensitivity of microglia to Cx3cr1-Cre-toxicity, wherein Cre-induction specifically in early postnatal microglia is detrimental for microglial development, proliferation and function. Tamoxifen (TAM) induced Cre-activity leads to microglial activation, type1-interferon (IFN-1) signaling and increased phagocytosis, causing aberrant synaptic pruning during early postnatal period and anxiety behavior in later age. The detrimental effects of Cre-induction are caused due to DNA-damage induced toxicity in microglia, and is limited to the early postnatal period, showing no detrimental effects in adult microglia. Thus, our study reveals the age-dependent vulnerability of microglia to Cre-activity, thereby highlighting age-dependencies of Cre-action, which could be especially applicable in the broader context of environment-responsive cell-types.
2021-12-08 | GSE190207 | GEO
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Brain lysate of adult WT, USP18ko, IFNAR1ko and USP18ko:IFNARko mice were analyzed
2015-04-20 | E-GEOD-61499 | biostudies-arrayexpress
Project description:Timecourse experiment (0hr, 2hr,6hr and 21hr) where RNA was extracted from non-rested PBMCs which were exposed to 4 different conditions- nothing (mock), interferon (IFN)gamma, IFN gamma and a non-specific antibody and IFN gamma with purified patient antibody. The purified patient antibody is demonstrated to have a specific anti-interferon gamma effect over time, with the expression profile in the arrays with IFN gamma plus patient antibody most closely resembling the mock arrays. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design
2005-09-17 | GSE3319 | GEO
Project description:Background Proteomic characterization of microglia has been limited by low yield and contamination by non-microglial proteins by magnetic-activated cell sorting (MACS) enrichment strategies. To determine whether a fluorescent-activated cell sorting (FACS)-based strategy overcomes these limitations, we compared microglial proteomes of MACS and FACS-based purified CD11b+ microglia in order to identify core sets of microglial proteins in adult mouse brain tissue. Results Quantitative multiplex proteomics by tandem mass tag mass spectrometry (TMT-MS) of MACS-enriched (N = 5) and FACS-purified (N = 5) adult wild-type CD11b+ microglia identified 1,791 proteins, of which 953 were differentially expressed indicating significant differences between both approaches. While the FACS-purified microglia proteome was enriched with cytosolic, endoplasmic reticulum and ribosomal proteins involved in protein metabolism and immune system functions, the MACS-enriched microglia proteome was enriched with proteins related to mitochondrial function and synaptic transmission. As compared to MACS, the FACS microglial proteome showed strong enrichment for canonical microglial proteins while neuron, astrocyte, and oligodendrocyte proteins were decreased. Interestingly, we observed enrichment of endothelial specific proteins in the FACS microglia proteome. By comparing FACS-purified microglia proteomes with transcriptomes, we observed highly concordant as well as highly discordant proteins that were abundant at the protein level but low at the transcript level. Conclusions We demonstrate that TMT-MS proteomics of FACS-purified adult microglia is superior to column-based enrichment approaches, resulting in purer and highly-enriched microglial proteomes. We also define core sets of highly-abundant adult microglial proteins including Moesin (Msn) that can guide future studies.
2020-05-11 | PXD015652 | Pride