Microglial aryl hydrocarbon receptor enhances phagocytic function and promotes remyelination in a model of multiple sclerosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210147 | GEO | 2022/08/03
REPOSITORIES: GEO
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Project description:Remyelination can occur naturally in demyelinating lesions, but often fails in human demyelinating diseases such as multiple sclerosis (MS). The function of the innate immune system is essential for the regenerative response, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory nuclear factor κB (NF-κB) dependent activation occurs in phagocytes rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88), the canonical adaptor for inflammatory signaling pathways downstream of toll-like receptors (TLRs). MyD88-deficient mice and zebrafish were impaired not only in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of tumor necrosis factor-α (TNF-α) in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is an evolutionary conserved mechanism necessary for degrading myelin debris, essential for inflammation resolution, and for initiating the secretion of pro-inflammatory myelin repair molecules.
2020-02-17 | PXD014625 | Pride
Project description:Remyelinating substances could be an essential supplement to immunomodulatory medications, optimizing the treatment of multiple sclerosis (MS) patients. Fingolimod is a sphingosine-1-phosphate receptor (S1PR) modulator and crosses the blood-brain barrier. Central nervous system (CNS) cells express S1PRs, and Fingolimod could theoretically improve CNS remyelination and be neuroprotective per se, but data are inconsistent. We used the cuprizone model for investigating the effect of fingolimod on remyelination and axonal damage by Immunohistochemistry and quantitative mass spectrometry. After three weeks of remyelination, fingolimod-treated mice had more mature oligodendrocytes in the secondary motor cortex than the placebo group. However, fingolimod did not at any time point affect remyelination or axonal damage. We conclude that fingolimod does not promote remyelination or protect against axonal injury or loss after cuprizone exposure.
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Project description:Purpose: The central nervous system (CNS) possesses intrinsic remyelination capabilities in response to demyelinating injury. However, this remyelination potential is diminished as demyelinating disease such as multiple sclerosis progresses overtime. To better understand myelin repair processes, the goal of this study was to determine temporal transcriptomic changes in cerebral white matter (corpus callosum) and gray matter (cortex and hippocampus) after acute and chronic demyelinating injury. The cuprizone mouse model of de- and remyelination was used for this investigation. Methods: Adult C57BL/6 mice were exposed to cuprizone diet (0.2%) for 3, 5 or 12 weeks followed by returning to normal diet for up to 12 weeks for recovery. Brain regions were dissected for bulk RNA-seq. Conclusion: RNA-seq analyses suggest common and distinct spatiotemporal transcriptional alterations during CNS demyelination and remyelination. Dataset for this study represents the first that covers gene expression landscapes of three brain regions over extended regenerative periods after chronic CNS demyelination.
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Project description:Mouse cuprizone (CPZ ) model of experimental de- and remyelination was applied to mimic demyelination pathology of multiple sclerosis. In order to identify differentially expressed microRNAs involved in de- and remyelination, the affected areas of corpus callosum were isolated from mice exposed to CPZ and conducted an Agilent microarray analysis. To induce demyelination, CPZ was administrated for four weeks. Spontaneous remyelination occurs as mice returned to the regular diet after four weeks feeding with CPZ (DEM_4w). Remyelination was examined at two time points: acute remyelination induced by four weeks CPZ feeding followed by two days of regular diet (two days remyelination: REM_2d), and full remyelination induced by four weeks CPZ feeding followed by two weeks of regular diet (two weeks remyelination: REM_2w). Control mice (C) were kept on a normal diet. The following groups representing de- and remyelinisation pathology in corpus callosum of CPZ-treated mice were compared: Demyelination: 4weeks CPZ: DEM_4w; Acute remyelination: 4 weeks CPZ +2 days UNTREATED: REM_2d; Full remyelination: 4 weeks CPZ +2 weeks UNTREATED: REM_2w; and UNTREATED control (C). The experiments were performed using 2-4 animals per groups.
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Project description:Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill-defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus, strain JHMV), we show that depletion of microglia after clearance of virus infection resulted in impaired myelin repair and prolonged clinical disease. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Further, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial function could not be compensated by infiltrating macrophages. Together, these results demonstrate key roles for microglia in debris clearance and the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.
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Project description:Peripheral viral infection disrupts oligodendrocyte homeostasis such that endogenous remyelination may be affected. Here, we demonstrate that influenza A virus infection perpetuated a demyelination- and disease-associated oligodendrocyte (OL) phenotype following cuprizone-induced demyelination that resulted in delayed OL maturation and remyelination in the prefrontal cortex. Furthermore, we assessed cellular metabolism ex-vivo, and found that infection altered brain OL and microglia metabolism in a manner that opposed the metabolic profile induced by remyelination. Specifically, infection increased glycolytic capacity of OLs and microglia, an effect that was recapitulated by LPS stimulation of mixed glia cultures. In contrast, mitochondrial respiration was increased in OLs during remyelination, which was similarly observed in OLs of myelinating P14 mice compared to adult and aged mice. Collectively, our data indicate that respiratory viral infection is capable of suppressing remyelination, and suggest that metabolic dysfunction of OLs is implicated in remyelination impairment.
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Project description:Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination occurring in these diseases. Here, we present a high-resolution snRNA-seq analysis of gene expression changes across all brain cells in this model. We define signatures of prototypic responses to demyelination and remyelination for each cell type, including anti-stress, anti-oxidant-, metabolic-, hypoxia-, IFN-, and IL-33-driven responses, and validate them at the protein level and in IL-33R-deficient mice. We identify related transcription regulators underpinning these pathways, including STAT3, NF-κB, OLIG1 and MAFB. Furthermore, snRNA- seq data provide novel insights into how various brain cell types connect and interact, defining complex circuitries previously unknown to impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency impacts the oligodendrocyte responses to demyelination. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelination and remyelination.
2023-03-27 | GSE204769 | GEO
Project description:Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination occurring in these diseases. Here, we present a high-resolution snRNA-seq analysis of gene expression changes across all brain cells in this model. We define signatures of prototypic responses to demyelination and remyelination for each cell type, including anti-stress, anti-oxidant-, metabolic-, hypoxia-, IFN-, and IL-33-driven responses, and validate them at the protein level and in IL-33R-deficient mice. We identify related transcription regulators underpinning these pathways, including STAT3, NF-κB, OLIG1 and MAFB. Furthermore, snRNA- seq data provide novel insights into how various brain cell types connect and interact, defining complex circuitries previously unknown to impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency impacts the oligodendrocyte responses to demyelination. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelination and remyelination.
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Project description:Myelin abnormalities, oligodendrocyte damage, and concomitant glia activation are common in demyelinating diseases of the central nervous system (CNS). The neurotoxicant cuprizone (CPZ) has been extensively used to create a mouse model of demyelination. However, the changes of miRNA expression and effects on behavior of cuprizone treatment have not been clearly reported. We have analyzed the behavioral changes of mice given a diet containing 0.2% cuprizone for 6 weeks. To evaluate the changes of miRNA expression in CPZ-induced demyelination compared with control, we performed the Affymetrix GeneChip® miRNA 4.0 Array. We identified 1348 and 1253 differentially expressed miRNAs for control and CPZ-treated mice, respectively. Furthermore, the expression of 240 miRNAs was significantly changed in CPZ-induced mice comparing with control mice. These results suggest that the changes of miRNA expression in vivo may provide a new potential remyelination therapeutic target.
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