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Microglia regulate cortical remyelination via ΤNFR1-dependent phenotypic polarization [scRNA-Seq]

ABSTRACT: Microglia are strongly implicated in demyelinating neurodegenerative diseases with increasing evidence for roles in protection and healing, but the mechanisms that control CNS remyelination are poorly understood. Here we show that microglia-specific deletion of TNFR1 and pharmacological inhibition of soluble TNF (solTNF) or downstream IL-1R allow maturation of highly activated disease-associated microglia with increased size and myelin phagocytosis capacity that accelerate cortical remyelination and motor recovery. Single cell transcriptomic analysis of cortex at disease onset reveal that solTNF inhibition enhances reparative IL-10-responsive, while preventing damaging IL-1-related signatures of disease-associated microglia. Longitudinal brain transcriptome analysis through disease reveal earlier recovery upon therapeutic loss of microglia TNFR1. Functional relevance of microglia inflammatory polarization pathways for disease is validated in vivo. Furthermore, disease-state microglia producing downstream IL-1/IL-18/NLRP3/CASP1 targets are identified in human demyelinating lesions. Overall, redirecting disease microglia polarization by targeting cytokines is a potential approach for improving CNS repair in demyelinating disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE278199 | GEO | 2024/11/12

REPOSITORIES: GEO

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Microglia regulate cortical remyelination via ΤNFR1-dependent phenotypic polarization [RNA-Seq]

Project description:Microglia are strongly implicated in demyelinating neurodegenerative diseases with increasing evidence for roles in protection and healing, but the mechanisms that control CNS remyelination are poorly understood. Here we show that microglia-specific deletion of TNFR1 and pharmacological inhibition of soluble TNF (solTNF) or downstream IL-1R allow maturation of highly activated disease-associated microglia with increased size and myelin phagocytosis capacity that accelerate cortical remyelination and motor recovery. Single cell transcriptomic analysis of cortex at disease onset reveal that solTNF inhibition enhances reparative IL-10-responsive, while preventing damaging IL-1-related signatures of disease-associated microglia. Longitudinal brain transcriptome analysis through disease reveal earlier recovery upon therapeutic loss of microglia TNFR1. Functional relevance of microglia inflammatory polarization pathways for disease is validated in vivo. Furthermore, disease-state microglia producing downstream IL-1/IL-18/NLRP3/CASP1 targets are identified in human demyelinating lesions. Overall, redirecting disease microglia polarization by targeting cytokines is a potential approach for improving CNS repair in demyelinating disorders.

2024-11-12 | GSE278137 | GEO

Temporal transcriptomic profiles of brain regions following acute and chronic demyelinating injury

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.

2023-04-03 | GSE212147 | GEO

Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

Project description:Microglia are necessary for CNS function during development and play roles in aging, Alzheimer’s Disease (AD) and the response to demyelinating injury. Mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Rieske Iron-Sulfur Protein (RISP) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation, and adult CNS function in vivo. Surprisingly, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA-seq analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia (DAM). Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with Amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

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PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [invitro]

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

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [exvivo]

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TNFR2 signaling regulates the immunomodulatory function of oligodendrocyte precursor cells

Project description:Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNg, IL1b and TNF we observed by RNA sequencing marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell-cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease.

2021-07-28 | GSE180604 | GEO

Gene expression in spinal cord microglia during demyelination and remyelination following neuroattenuated JHMV infection

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.

2020-02-07 | GSE144911 | GEO

Single-cell RNA sequencing reveals the diversity of the immunological landscape in response to murine coronavirus infection of the central nervous system

Project description:Intracranial (i.c.) infection of susceptible C57BL/6 mice with a neurotropic JHM strain mouse hepatitis virus (a member of the Coronaviridae family) results in acute encephalomyelitis and viral persistence associated with an immune-mediated demyelinating disease. The present study was undertaken to better understand the molecular pathways evoked during innate and adaptive immune responses as well as the chronic demyelinating stage of disease in response to JHMV infection of the central nervous system (CNS). Using single cell RNA sequencing analysis (scRNAseq) on flow-sorted CD45-positive cells (CD45+) enriched from brains and spinal cords of experimental mice, we demonstrate the heterogeneity of the immune response as determined by unique molecular signatures and pathways involved in effective anti-viral host defense. Furthermore, we identify potential genes involved in contributing to demyelination as well as remyelination being expressed by both microglia and macrophages. Collectively, these findings emphasize the diversity of the immune response and molecular networks at defined stages following viral infection of the CNS.

2021-08-09 | GSE158269 | GEO

IL4 improves white matter repair after stroke

Project description:The repair of white matter damage is of paramount importance for functional recovery after brain injuries.We report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 days after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific PPARγ knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the CNS, which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.

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Transcription profiling of brain tissue from wild type and casp1 knock-out mice treated with lipopolysaccharide or sodium chloride

Project description:The systemic inflammatory response syndrome (SIRS) is a life-threatening medical condition characterized by a severe and generalized inflammatory state that can lead to multiple organ failure and shock. The central nervous system (CNS) regulates many features of SIRS, such as fever, cardiovascular and neuroendocrine responses. <br> <br> Central and systemic manifestations of SIRS can be induced by LPS or interleukin-1ß (IL-1ß) administration. The crucial role of IL-1ß in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1ß convertase), a protease that cleaves pro-IL-1ß into mature IL-1ß. Indeed, casp1 knockout (casp1-/-) mice survive lethal doses of LPS. The key role of IL-1ß in sickness behavior and its de-novo expression in the CNS during inflammation led us to test the hypothesis that IL-1ß plays a major role modulating the brain transcriptome during SIRS. <br> <br> We show here a genetic background environment effect caused by LPS administration in casp1-/- when compared to wild-type mice affecting the expression several genes, such as chemokines, GTPases, the metalloprotease ADAMTS1, IL-1RA, the inducible nitric oxide synthase (NOS2) and cyclooxygenase-2 (COX-2) were differentially increased by. Our findings may contribute to the understanding of the molecular changes that take place within the CNS during sepsis and SIRS and the development of new therapies for these serious conditions. Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated, and indicate that casp1 might be a potential therapeutic target for such disorders.

2008-03-02 | E-MEXP-1017 | biostudies-arrayexpress

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