Astrocyte-mediated Neuroinflammation in Multiple Sclerosis

03-Mar-2020

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelination and neurodegeneration. Previous work has examined how neurons, microglia, and other glial and myeloid cell types are involved in the pathogenesis of MS or autoimmune encephalomyelitis (EAE), its preclinical model system, though the impact of individual astrocyte populations remains unresolved. Now, as described in their recent Nature study, Wheeler et al. utilized a series of cutting-edge techniques to identify a subpopulation of astrocytes that possess a proinflammatory phenotypic signature present in both EAE and human MS patient samples (1). Beginning with the EAE model system, the authors performed single-cell RNA sequencing and cell-specific Ribotag RNA profiling, in vivo CRISPR-Cas9-based genetic manipulations, and a host of chromatin interrogation protocols to reveal the molecular features of a particular cluster of astrocytes in EAE with diminished NRF2 levels. As NRF2 functions to counter proinflammatory and neurotoxic pathways, its decrease in these astrocytes results in CNS inflammation. Furthermore, the authors found that the small MAF protein MAFG, which can interfere with NRF2-driven transcription, is overexpressed in EAE astrocytes. MAFG impacts DNA methylation through its cofactor MAT2α, thereby dictating the suppression of anti-inflammatory mechanisms in these astrocytes. In addition, GM-CSF secreted by T cells that move to the CNS in EAE and MS appears to exacerbate this proinflammatory effect. Clear parallels were noted in human MS samples. Thus, the authors have identified astrocytes in EAE and MS that contribute to CNS inflammation by way of a proinflammatory expression profile stemming from suppressed anti-inflammatory transcriptional mechanisms.

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