Brain macrophages adopt distinct profiles prior to demyelination in multiple sclerosis
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE179427 | GEO | 2022/02/02
REPOSITORIES: GEO
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Project description:In this project we focused on white matter injury in relapsing remitting MS. We concentrated on material obtained from patients who suffered from fulminant active MS to identify possible sources for ROS production in relation to demyelination and neurodegeneration. To identify possible sources for ROS production in relation to demyelination and neurodegeneration in MS, we used genome wide microarray analysis of gene expression in carefully dissected lesion areas of patients with fulminant acute MS. Preceding the gene expression profiling all cases were characterized histologically and areas of interest were identified. We included 4 control cases, 2 active MS cases were we separated 3 distinct lesions areas (NAWM, initial lesion and early demyelinated lesion) and 1 active MS case were we separated 2 distinct lesion areas (NAWM and early demyelinated lesion). The RNA was isolated from those areas, amplified and hybridized to Agilent G4112A whole genome microarrays.
2011-10-12 | E-GEOD-32915 | biostudies-arrayexpress
Project description:Multiple Sclerosis (MS) is a complex disease of the CNS believed to require one or more environmental triggers and is characterized by episodic formation of inflammatory demyelinating lesions in the brain and spinal cord. Gut dysbiosis is a common feature in MS and here, using enhanced and quantitative PCR detection, we show that people with MS are more likely to harbor and have higher abundance of epsilon toxin (ETX)-producing strains of Clostridium perfringens within their gut microbiome compared to healthy controls (HC). MS patient-derived isolates produce functional ETX and have a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, we find that ETX can substitute for PTX in disease induction. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE results in multifocal demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the lesion distribution observed in MS. Transcriptional profiles from CNS endothelial cells reveal ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings support ETX-producing strains of C. perfringens as biologically plausible pathogens in MS to trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.
2023-03-31 | GSE223137 | GEO
Project description:Background. Multiple Sclerosis is a chronic inflammatory disease of the central nervous system (CNS) characterized by autoimmune demyelination and subsequent neuro-axonal degeneration. Despite major progress in deciphering MS immunopathogenesis and treating early stages of disease, CNS-confined processes underpinning later progressive form of MS remain elusive, alluding to the poor accessibility to the target organ. We and others have demonstrated the reliability of profiling DNA methylation, a stable epigenetic marker of genome activity, in neuronal nuclei or bulk tissue to capture relevant molecular changes underlying MS neuropathology. In this study, we examined DNA methylation changes occurring in the normal appearing white matter (NAWM) glial cells of MS patients in comparison to white matter (WM) of non-neurological controls (NNC). Results. We profiled DNA methylation in NeuN-negative nuclei of glial cells, isolated from 38 postmortem NAWM specimens of MS patients (n=8) in comparison to WM of NNC individuals (n=14), using Infinium MethylationEPIC BeadChip. We applied reference-free cell type deconvolution to further reduce cellular heterogeneity and identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the affected genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation as well as signaling pathways, such as Rho, Wnt and TGF-β signaling. A fraction of these changes affected genes which displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Gene ontology analysis of differentially methylated genes according to their constitutive cell type-specific expression in glial cells attributed alteration of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Conclusion. Our findings strongly suggest that NAWM glial cells are highly active, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.
2022-02-10 | GSE166207 | GEO
Project description:In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevent the activation of neuroinflammatory reactive astrocytes while promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin regenerative and supportive agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.
2024-10-29 | GSE280579 | GEO
Project description:In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevent the activation of neuroinflammatory reactive astrocytes while promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin regenerative and supportive agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.
2024-10-29 | GSE280578 | GEO
Project description:People living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils.
2022-04-29 | GSE201568 | GEO
Project description:Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. Demyelinating lesions are associated with infiltrating T lymphocytes, bone marrow-derived macrophages (BMDM), and activated resident microglia. Tissue damage is thought to be mediated by T cell produced cytokines and chemokines, which activate microglia and/or BMDM to both strip myelin and produce toxic factors, ultimately damaging axons and promoting disability. However, the relative contributions of BMDM and microglia to demyelinating pathology are unclear, as their identification in MS tissue is difficult due to similar morphology and indistinguishable surface markers when activated. The CD4 T cell-induced autoimmune murine model of MS, experimental autoimmune encephalitis (EAE), in which BMDM are essential for demyelination, has revealed pathogenic and repair-promoting phenotypes associated with BMDM and microglia, respectively. Using a murine model of demyelination induced by a gliatropic coronavirus, in which BMDM are redundant for demyelination, we herein characterize gene expression profiles of BMDM versus microglia associated with demyelination. While gene expression in CNS infiltrating BMDM was upregulated early following infection and subsequently sustained, microglia expressed a more dynamic gene profile with extensive mRNA upregulation coinciding with peak demyelination after viral control. This delayed microglia response comprised a highly pro-inflammatory and phagocytic profile. Furthermore, while BMDM exhibited a mixed phenotype of M1 and M2 markers, microglia repressed the vast majority of M2-markers. Overall, these data support a pro-inflammatory and pathogenic role of microglia temporally remote from viral control, whereas BMDM retained their gene expression profile independent of the changing environment. As demyelination is caused by multifactorial insults, our results highlight the plasticity of microglia in responding to distinct inflammatory settings, which may be relevant for MS pathogenesis.
2022-10-02 | GSE214472 | GEO
Project description:In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1, and ANO4. Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16, and OLR1, and lipid uptake, such as CHIT1, GPNMB, and CCL18. Except CCL18, these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion.
2018-01-01 | GSE108000 | GEO
Project description:Multiple Sclerosis (MS) is a neuroinflammatory disease characterized by demyelinated lesions in the CNS. Remyelination in MS is variable between individuals and tends to become less efficient with aging. Microglia and astrocytes are known to have critical roles in MS pathogenesis, but to what extent their activity is altered by remyelination failure remains unclear. To determine the effects of demyelination on neuroinflammation, we use two mouse models that genetically ablate myelinating oligodendrocytes. We use the Plp1-CreERT mouse line crossed with the Myrf fl/fl mouse line to induce genetic demyelination throughout the CNS following adult tamoxifen administration. Subsequent remyelination is mediated by the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) to newly formed oligodendrocytes. To assess the consequences of remyelination failure, we deleted Myrf from both mature oligodendrocytes and OPCs using Myrf fl/fl; Sox10-CreERT mice, which both induces demyelination and impairs subsequent remyelination. To characterize the glial cells in these demyelinated mice, we performed single-nucleus RNA-sequencing (snRNAseq) of optic nerves at peak demyelination, generating an atlas of non-neuronal cells including oligodendrocyte lineage cells, astrocytes, microglia, endothelial cells, pericytes, arachnoid barrier cells, vascular and leptomeningeal cells.
2024-09-12 | GSE243788 | GEO
Project description:Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS), where ongoing demyelination and remyelination failure are the major factors for progressive neurological disability. In this report, we employed a comprehensive proteomic approach and immunohistochemical (IHC) validation to gaininsight into the pathobiological mechanisms that may be associated with the progressive phase of MS disease. Isolated proteins from myelinated regions, demyelinated white matter lesions (WMLs), and grey-matter lesions (GMLs) of well-characterized progressive MS brain tissues were subjected to label-free quantitative mass spectrometry (LFQ-MS). Using a system-biology approach, we detected increased expression of proteins belonging to mitochondrial electron transport complexes and oxidative phosphorylatio pathway in WMLs. Intriguingly, many of these proteins and pathways had opposite expression patterns in GMLs of progressive MS brains. A comparison to the huma MitoCarta database mapped the mitochondrial proteins to mitochondrial subunits in both WMLs and GMLs. Taken together, we provide evidence of opposite expression of mitochondrial proteins in response to demyelination of white- and grey-matter regions in progressive MS brain.
2021-12-21 | PXD029285 | Pride