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Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [spinal cord]

ABSTRACT: Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and non-canonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and inflammation which are highly correlated with the amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking Drd2 in neurons. Together, our findings reveal previously uncharted roles for a DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE205291 | GEO | 2022/07/15

REPOSITORIES: GEO

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Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [astrocyte]

Project description:Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and non-canonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and inflammation which are highly correlated with the amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking Drd2 in neurons. Together, our findings reveal previously uncharted roles for a DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.

2022-07-15 | GSE205290 | GEO

RNA-seq for understanding astrocyte S1P1 signaling

Project description:Astrocytic S1P1 has been previously shown to be essential for FTY720 (an orally delivered drug for MS) efficacy (CNS), in addition to its well-known immunological mechanisms of action. FTY720-P (an analogue of S1P) is a functional antagonist to S1P1. TetTag c-Fos reporter mice displayed temporal and spatial GFP-labeling of astrocytic nuclei under experimental autoimmune encephalomyelitis (EAE) pathology. We generated astrocyte conditional S1P1-KO mice in c-Fos background (S1P1-AsCKOfos). In search of essential factors controlled by S1P-S1P1 signaling in astrocytes, we employed nuclear RNA-seq using RNA of DAPI+NeuN-GFP+ nuclei isolated from spinal cords (SCs) of EAE-induced WTfos, S1P1-AsCKOfos, and FTY720-treated WTfos mice.

2022-05-17 | GSE99114 | GEO

Genome-wide analysis of the transcriptional profile of astrocytes during EAE in Gfap-TdTomato mice by scRNA-seq [scRNA-seq 2]

Project description:We identify astrocyte heterogeneity during EAE in B6 mice. Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.

2020-02-12 | GSE129763 | GEO

Genome-wide analysis of the transcriptional profile of astrocytes across EAE by CNS region in Gfap-Cre;Ribotag(f/f) mice uisng Ribotag immunoprecipitation.

Project description:We identify pathways regulated in astrocytes across EAE by CNS region. Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.

2020-02-12 | GSE130118 | GEO

Genome-wide analysis of chromatin profile in astrocytes isolated from EAE mice transduced with astrocyte-specific Mafg-targeting or non-targeting lentiviruses [ATAC-seq]

Project description:Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets. We report MAFG regulation of pathogenic activities in astrocytes during EAE.

2020-02-12 | GSE129608 | GEO

Genome-wide analysis of MAFG binding in astrocytes during EAE [ChIP-seq]

Project description:We report MAFG recruitment to ARE elements in astrocytes during EAE compared to naïve mice Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.

2020-02-12 | GSE129607 | GEO

Genome-wide analysis of DNA methylation profile in astrocytes isolated from naïve mice or EAE mice transduced with astrocyte-specific Mafg-targeting or non-targeting lentiviruses [WGBS]

Project description:We report MAFG regulation of DNA methylation in astrocytes during EAE. Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.

2020-02-12 | GSE129606 | GEO

Genome-wide analysis of the transcriptional profile of WT and CSF2RB astrocyte conditional KO during EAE in B6 mice [Csf2rb RNA-seq]

Project description:We identify pathways regulated by Csf2rb in astrocytes during EAE Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.

2020-02-12 | GSE129773 | GEO

Genome-wide analysis of the transcriptional profile of WT and Nfe2l2 KD astrocytes during EAE in B6 mice [Nrf2 RNA-seq]

Project description:We identify pathways regulated by Nfe2l2 in astrocytes during EAE Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.

2020-02-12 | GSE129774 | GEO

Genome-wide analysis of the transcriptional profile of the CNS during EAE in B6 mice by scRNA-seq [scRNA-seq]

Project description:We identify cellular heterogeneity during EAE in B6 mice. Multiple sclerosis (MS) is an autoimmune neurologic disease leading to demyelination and neurologic dysfunction controlled by both genetic and environmental factors. In addition to CNS-infiltrating immune cells, CNS-resident cells, such as astrocytes, are thought to play an important role in MS pathogenesis. However, a comprehensive understanding of the extent to which gene expression is disrupted in astrocytes is not known. Here, we implement single-cell RNA sequencing, in vivo genetic perturbations, cell-specific RNA profiling by Ribotag, as well as single-cell RNA sequencing of human MS patient samples to identify a transcriptional regulatory network in astrocytes that controls the pathogenesis of EAE and potentially, MS. We defined an astrocyte subpopulation characterized by expression of the small Maf protein, MAFG, which represses NRF2-driven antioxidant mechanisms and promotes EAE pathogenesis. Mechanistically, MAFG suppresses NRF2-dependent antioxidant genetic programs by cooperating with its cofactor, MAT2a, to promote DNA methylation in the context of CNS inflammation, which in turn increases pathogenic signaling processes in astrocytes. MAFG/MAT2a astrocytes are controlled by GM-CSF signaling, which drives EAE pathogenesis and MAFG expression. MAFG is activated in astrocytes derived from MS patients, which are characterized by DNA methylation programs, pro-inflammatory signaling processes including GM-CSF signaling, and repressed NRF2 activation. Together, these data create a transcriptional and epigenetic framework to analyze CNS inflammation in MS and may provide new therapeutic targets.

2020-02-12 | GSE129609 | GEO

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