Transcriptome of human primary macrophages from X-linked adrenoleukodystrophy patients and healthy controls before and after long-term myelin phagocytosis
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ABSTRACT:
PROVIDER: PRJNA1027446 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR22148778.fastq.gz | Fastqsanger.gz | |||
| SRR22148779.fastq.gz | Fastqsanger.gz | |||
| SRR22148780.fastq.gz | Fastqsanger.gz | |||
| SRR22148781.fastq.gz | Fastqsanger.gz | |||
| SRR22148782.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptome of human primary macrophages from healthy controls after long-term myelin phagocytosis
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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
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.
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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. 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.
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Project description:CD14+ monocytes were isolated from the blood of healthy human donors by Ficoll density-gradient centrifugation, magnetic cell sorting and LS column systems. CD14+ monocytes were in vitro differentiated to macrophages by culturing the cells for 7 days in RPMI medium containing 10% FCS, 1% penicillin/streptomycin, 1% glutamine, 1% Fungizone and supplemented with 50 ng/ml human macrophage-colony stimulating factor (M-CSF) in the presence or absence of myelin isolated from brain tissue of 6-8 week-old wild-type C57BL6/J mice.
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2023-10-12 | GSE245235 | GEO
Project description:Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD) collectively represent the majority of dementia cases worldwide. While these subtypes share clinical, genetic, and pathological features, their transcriptomic similarities and differences remain poorly understood. We applied single-nucleus RNA-sequencing (snRNA-seq) to prefrontal cortex samples from individuals with non-cognitive impairment control (NCI), and dementia subtypes (AD, DLB, and PDD) to investigate cell type-specific gene expression patterns and pathways underlying pathological similarities and differences across dementia subtypes. SnRNA-seq findings were validated through RNAscope, immunohistochemistry, and additional biochemical analyses in human tissues and cellular models. snRNA-seq analysis revealed elevated microglial proportions across all dementia subtypes compared to NCI. Further analysis of cell type-specific transcriptomes identified overlapping differentially expressed genes (DEGs) between microglia and oligodendrocytes across all dementia subtypes. While AD showed molecular similarities to NCI, PDD and DLB were clustered more closely together, sharing a greater number of DEGs and related pathways, predominantly associated with microglia. Investigation of interactions between microglia and oligodendrocytes revealed a distinct myelin-enriched microglia (MEM) subcluster in all dementia subtypes. MSR1, a gene encoding a scavenger receptor, was upregulated in microglia across all dementia subtypes, along with its associated gene HSPA1A in oligodendrocytes. RNAscope supported the potential interaction between microglia and oligodendrocytes, where these cells were in closer proximity to each other in human cortical tissues of PDD compared to NCI. MSR1 expression was significantly increased in cortical primary microglia from PD mice compared with non-transgenic (NTg) mice. Additionally, the expression of myelin-associated genes (MBP, MOBP and PLP1) was significantly upregulated in PD microglia compared to NTg, supporting the presence of MEM. Furthermore, MSR1-positive microglia colocalised with MBP in cortical tissue of PDD patients, suggesting a functional role of MSR1 in myelin debris clearance. Overexpression of MSR1 in microglial cells enhanced their phagocytic activity toward myelin, and reciprocally, myelin treatment upregulated MSR1 protein levels, indicating enhanced MSR1-mediated myelin phagocytosis.
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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.
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Project description:Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD). The severest form, inherited dysfunction of the VLCFA transporter ABCD1, underlying X-ALD, causes brain myelin destruction with infiltration of pro-inflammatory skewed monocytes/macrophages. How VLCFA levels relate to macrophage activation is unclear. Using whole transcriptome sequencing of X-ALD macrophages, we revealed that VLCFAs prime human macrophage membranes for inflammation and increase factors involved in chemotaxis and invasion. When applied externally, mimicking lipid destruction in X-ALD lesions, VLCFAs did not activate toll-like receptors in healthy cells but provoked pro-inflammatory responses through scavenger receptor CD36-mediated uptake, cumulating in JNK signalling and expression of matrix degrading enzymes and chemokine release. Following pro-inflammatory LPS-activation, VLCFA accumulated in healthy macrophages but were rapidly cleared with onset of resolution by increasing VLCFA degradation through liver-X-receptor mediated upregulation of ABCD1. ABCD1 deficiency impaired VLCFA homeostasis and prolonged pro-inflammatory gene expression. Our study uncovers a pivotal role for ABCD1, a protein linked to neuroinflammation, and associated peroxisomal VLCFA degradation in regulating macrophage plasticity.
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