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Microglia regulate cortical remyelination via ΤNFR1-dependent phenotypic polarization [RNA-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: GSE278137 | GEO | 2024/11/12

REPOSITORIES: GEO

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

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

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