Transcriptomic profiling of peroxisome-deficient, myelin debris-laden macrophages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1074086 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27887244_1.fastq.gz | Fastqsanger.gz | |||
| SRR27887244_2.fastq.gz | Fastqsanger.gz | |||
| SRR27887245_1.fastq.gz | Fastqsanger.gz | |||
| SRR27887245_2.fastq.gz | Fastqsanger.gz | |||
| SRR27887246_1.fastq.gz | Fastqsanger.gz |
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Project description:Study objective was to investigate the molecular underpinnings of how Pex5 and peroxisome integrity facilitated the demyelination response in myeloid cells. We investigated the transcriptomic changes related to myelin debris uptake in the context of disrupted peroxisome integrity using Pex5 deficient bone marrow derived macrophages.
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Project description:Sterile neuroinflammation is a major driver of multiple neurological diseases. Myelin debris, which is released from the damaged myelin sheaths during demyelination, can act as an inflammatory stimulus to promote sterile inflammation and neurological pathologies, but the mechanism is poorly understood. Here, we show that lysophosphatidylserine (LysoPS)-GPR34 axis plays a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation. Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS. Both myelin debris and LysoPS promoted microglia to produce IL-1and IL-6 via GPR34 and its downstream PI3K-AKT and ERK signaling. In vivo, LysoPS production and GPR34 signaling were found to be essential for neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke. Importantly, pharmacologic blockade of GPR34 showed potential therapeutic effects on these disease models. Thus, our results identify GPR34 as a key receptor to sense myelin debris and promote neuroinflammation, and suggest it as a potential target for demyelination-associated diseases.
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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.
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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.
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Project description:GPR34 senses myelin debris to promote neuroinflammation and pathology
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Project description:Tumors growing in metabolically-challenged environments, such as glioblastoma in the brain, are particularly reliant on cross-talk with their tumor microenvironment (TME) to satisfy their high energetic needs. However, the intricacies of this metabolic interplay and the consequences on immune cell subset diversity and function remain largely unexplored. We interrogated the heterogeneity of the glioblastoma TME using single cell multi-omics analyses in preclinical glioblastoma mouse models and patient samples, and identified metabolically-rewired tumor-associated macrophage (TAM) subpopulations that fuel glioblastoma malignancy. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their increased lipid metabolism activity and cholesterol storage, are epigenetically rewired, display immunosuppressive features and are enriched in the aggressive mesenchymal glioblastoma subtype. In response to TME-derived cues triggering liver-X-receptor (LXR) expression, macrophages increase engulfment of cholesterol-rich myelin debris and acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Furthermore, LLM content predicts clinical outcomes and immune checkpoint blockade response in glioblastoma patients and other cancer types. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression in a subtype- and microanatomical niche-dependent manner, thereby laying a framework for the discovery of targetable metabolic vulnerabilities in glioblastoma.
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Project description:Tumors growing in metabolically-challenged environments, such as glioblastoma in the brain, are particularly reliant on cross-talk with their tumor microenvironment (TME) to satisfy their high energetic needs. However, the intricacies of this metabolic interplay and the consequences on immune cell subset diversity and function remain largely unexplored. We interrogated the heterogeneity of the glioblastoma TME using single cell multi-omics analyses in preclinical glioblastoma mouse models and patient samples, and identified metabolically-rewired tumor-associated macrophage (TAM) subpopulations that fuel glioblastoma malignancy. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their increased lipid metabolism activity and cholesterol storage, are epigenetically rewired, display immunosuppressive features and are enriched in the aggressive mesenchymal glioblastoma subtype. In response to TME-derived cues triggering liver-X-receptor (LXR) expression, macrophages increase engulfment of cholesterol-rich myelin debris and acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Furthermore, LLM content predicts clinical outcomes and immune checkpoint blockade response in glioblastoma patients and other cancer types. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression in a subtype- and microanatomical niche-dependent manner, thereby laying a framework for the discovery of targetable metabolic vulnerabilities in glioblastoma.
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