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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of myelin-phagocytosing macrophages

ABSTRACT: Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. During active multiple sclerosis foamy macrophages and microglia, containing degenerated myelin, are abundantly found in demyelinated areas. Recent studies have described an altered macrophage phenotype after myelin internalization. However, by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression is unclear. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes in pathways involved in migration, phagocytosis and inflammation. More interestingly, we show that myelin internalization induces the expression of genes involved in liver X receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. Additionally, myelin suppresses the production of pro-inflammatory mediators, like nitric oxide and IL-6, by macrophages in a similar manner as a liver X receptor agonist. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in multiple sclerosis. Rat peritoneal macrophages were left untreated (n=5) or treated with isolated myelin (n=5) for 3 days. Both untreated and myelin-treated macrophages were subsequently stimulated with IFNM-RM-/ and IL1-M-NM-2 for 9 hours.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Jeroen Bogie

PROVIDER: E-GEOD-34811 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression profiling of myelin-phagocytosing macrophages

Project description:Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. During active multiple sclerosis foamy macrophages and microglia, containing degenerated myelin, are abundantly found in demyelinated areas. Recent studies have described an altered macrophage phenotype after myelin internalization. However, by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression is unclear. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes in pathways involved in migration, phagocytosis and inflammation. More interestingly, we show that myelin internalization induces the expression of genes involved in liver X receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. Additionally, myelin suppresses the production of pro-inflammatory mediators, like nitric oxide and IL-6, by macrophages in a similar manner as a liver X receptor agonist. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in multiple sclerosis.

2012-08-20 | GSE34811 | GEO

Retinoid X Receptor activation reverses the age-related deficiency in myelin debris phagocytosis and enhances remyelination

Project description:The efficiency of central nervous system (CNS) remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study we show that expression of genes involved in the retinoid X receptor (RXR) pathway are decreased with aging in myelin-phagocytosing cells. Loss of RXR function in young macrophages mimics aging by delaying remyelination after experimentally-induced demyelination, while RXR agonists partially restore myelin debris phagocytosis in aged macrophages. The FDA-approved RXR agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in aging human monocytes to a more youthful profile. These results reveal the RXR pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics. 24 Human CD14+ monocyte-sorted PBMC samples representing 4 Healthy Volunteers (HV) and 4 Multiple Sclerosis (MS) patients under 3 different treatment conditions. Condition 1 = (-) Phagocystosis (-) Bexarotene. Condition 2 = (+) Phagocystosis (-) Bexarotene. Condition 3 = (+) Phagocystosis (+) Bexarotene.

2015-11-04 | E-GEOD-66988 | biostudies-arrayexpress

Loss of HDAC11 leads to reduced secretion of MCP-1 and less severe EAE

Project description:HDAC11 regulates IL-10 expression and overexpression of HDAC11 in antigen presenting cells (APCs) leads to a pro-inflammatory phenotype. Conversely, loss of HDAC11 leads to upregulation of IL-10 and immune tolerance. HDAC11 overexpression is also associated with inflammatory diseases including multiple sclerosis. Hence we wished to determine the inflammatory mediators regulated by HDAC11. We used microarray to determine gene expression profile of macrophages from WT and HDAC11 knockout mice. Thioglycollate induced-peritoneal macrophages obtained from WT and HDAC11 knockout mice were used for total RNA extraction to determine changes in gene expression levels in macrophages from WT and HDAC11 knockout mice.

2014-03-31 | E-GEOD-56366 | biostudies-arrayexpress

RNA sequencing of monocytes and microglia from mice with experimental autoimmune encephalomyelitis illustrates a changing phenotype with disease course

Project description:The role of microglia and infiltrating monocytes in experimental autoimmune encephalomyelitis (EAE) pathogenesis has been controversial. To gain insight into their respective roles, we developed a method for differentiating between microglia and infiltrating monocytes in the CNS using CD44. We used this system to monitor changes in cell number, activation status, and gene expression by RNA sequencing (RNA-Seq) over the course of disease. This in vivo characterization and RNA-Seq dataset improves our understanding of myeloid cell biology in the brain under inflammatory conditions and may lead to strategies to identify therapies for inflammatory pathways active in neuroinflammatory diseases. Pooled samples from 10 mice were analyzed for both microglia and monocytes at distinct timepoints post EAE inducation. Peritoneal macrophages were isolated and analyzed for five samples, and also in a pool.

2014-10-20 | E-GEOD-59725 | biostudies-arrayexpress

Pro-inflammatory activity following demyelinating injury is required for phagocytic function and oligodendrocyte formation

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2020-02-17 | PXD014625 | Pride

White matter integrity requires continuous myelin synthesis at the inner tongue

Project description:Myelin, the electrically insulating axonal sheath, is composed of lipids and proteins with exceptionally long lifetime. Using 3D electron microscopy, mass spectrometry imaging, and quantitative proteome analysis, we addressed the question how myelin function is affected by myelin turnover. We studied the integrity of myelinated tracts after experimentally preventing the formation of new myelin in the CNS of adult mice by an inducible myelin basic protein (Mbp) null allele. Recombined oligodendrocytes continued to express myelin genes, but failed to establish MBP-dependent compaction of myelin sheaths. Abundance changes of myelin proteins upon Mbp ablation were analyzed in whole optic nerve lysates at different time points and compared with shiverer mice. This naturally occurring mutant is inable to developmentally form compact myelin due to the lack of MBP and served as proxy for the demyelination endpoint. Label-free protein quantification using an ion mobility-enhanced data-independent acquisition (DIA) workflow with alternating low and elevated energy (referred to as UDMS^E) revealed that numerous myelin proteins are reduced in abundance, while microglia and astrocyte markers were increased, indicative of neuropathology. Taken together, we observed an axonal pathology with about 50% myelin loss after 20 weeks and concluded that functional axon-myelin units require the continuous incorporation of new myelin membranes.

2022-01-14 | PXD025180 | Pride

Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes

Project description:Microglia are brain-resident, myelin-phagocytosing cells, yet their role in lesion initiation in grey and white matter regions in multiple sclerosis (MS) is unclear. We isolated primary microglia from both, occipital cortex and corpus callosum, of 10 MS and 11 control donors and studied their transcriptional profile by RNA sequencing, thereby identifying regional and MS-associated changes. Identification of pathways underlying regional differences showed a relatively increased type I interferon response in cortical grey matter microglia, while white matter microglia more highly expressed NF-κB pathway genes. In normal-appearing white matter MS tissue, lipid metabolism genes were increased, suggesting processing of myelin by microglia already in areas seemingly devoid of MS pathology. Normal-appearing grey matter MS microglia showed increased activation of glycolysis and metal ion homeostasis, possibly reflecting microglia reacting to iron depositions. Notably, expression of genes associated with microglia homeostasis were hardly changed, suggesting that subtle regional changes in MS-associated microglia do not yet affect their resting state.

2019-03-13 | GSE111972 | GEO

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

Transcription profiling of mouse Pac1+/+ versus Pac1-/- TG-macrophages treated with LPS - 6h

Project description:LPS-stimulated macrophages from Pac1+/+ and Pac1-/- mice were compared to assess gene expression changes in the absence of PAC-1 (also known as Dual specificity phosphatase 2). Experiment Overall Design: Age matched Pac1+/+ and Pac1-/- littermates were used to obtain equal numbers of thiolycollate-elicited macrophages. Pure populations of macrophages were stimulated with 100 ng/ml of LPS for 6 hours. 6 hours was chosen to assess mainly inflammatory gene expression.

2008-06-12 | E-GEOD-3993 | biostudies-arrayexpress

Red blood cells from mice on high fat diet induce macrophage activation during phagocytosis

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2013-08-28 | E-GEOD-50240 | biostudies-arrayexpress

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