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GPR34 senses myelin debris to promote neuroinflammation and pathology

ABSTRACT: GPR34 senses myelin debris to promote neuroinflammation and pathology

PROVIDER: PRJNA802043 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17830294_1.fastq.gz	Fastqsanger.gz
	SRR17830294_2.fastq.gz	Fastqsanger.gz
	SRR17830295_1.fastq.gz	Fastqsanger.gz
	SRR17830295_2.fastq.gz	Fastqsanger.gz
	SRR17830296_1.fastq.gz	Fastqsanger.gz

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GPR34 senses myelin debris to promote neuroinflammation and pathology

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-1and 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.

2025-01-30 | GSE195741 | GEO

Transcriptomic profiling of peroxisome-deficient, myelin debris-laden macrophages

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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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.

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

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Project description:Axon degeneration and neurological dysfunction in myelin diseases is often attributed to loss of myelin. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. We have previously shown in mice that distinct defects in the proteolipid protein 1 gene result in axonal damage which is largely driven by cytotoxic T cells targeting myelinating oligodendrocytes. Here we show in these mutants that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce aberrant cytoskeletal plasticity within myelinating glial processes and constriction of axons at paranodal domains. Our study identifies detrimental axon-glia interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

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