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Review
. 2019 Jan 2;9(1):a029009.
doi: 10.1101/cshperspect.a029009.

Regulation of Astrocyte Functions in Multiple Sclerosis

Michael A Wheeler  1 , Francisco J Quintana  1   2
Affiliations
Review

Regulation of Astrocyte Functions in Multiple Sclerosis

Michael A Wheeler et al. Cold Spring Harb Perspect Med. .

Abstract

Astrocytes play complex roles in health and disease. Here, we review recent findings on molecular pathways that control astrocyte function in multiple sclerosis (MS) as well as new tools for their investigation. In particular, we describe positive and negative regulators of astrocyte-mediated pathogenesis in MS, such as sphingolipid metabolism and aryl hydrocarbon receptor signaling, respectively. In addition, we also discuss the issue of astrocyte heterogeneity and its relevance for the contribution of astrocytes to MS pathogenesis. Finally, we discuss how new genomic tools could transform the study of astrocyte biology in MS.

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Figures

Figure 1.
Figure 1.
Cellular cross talk in the central nervous system (CNS). Microglia activated by infection, neurodegeneration, or other triggers produce molecules that induce a proinflammatory (A1) phenotype in astrocytes. A1 astrocytes prevent synapse formation and decrease neurotrophic support, also impairing oligodendrocyte function. Proinflammatory molecules act on astrocytes to boost sphingolipid metabolism, nuclear factor (NF)-κB transcriptional activity, and cytokine production while down-regulating anti-inflammatory aryl hydrocarbon receptor (AHR) transcriptional activity. As a result, astrocytes secrete neurotoxic molecules such as tumor necrosis factor α (TNF)-α and nitric oxide (NO), which amplify this neurotoxic state, and also CCL2, which recruits proinflammatory immune cells. IL, Interleukin.
Figure 2.
Figure 2.
Astrocyte function in multiple sclerosis (MS). Environmental factors described to affect MS onset and progression, such as environmental toxins, the diet, metabolites generated by the commensal flora, and sunlight, may act on astrocytes to modulate MS-relevant pathogenic functions.
Figure 3.
Figure 3.
Tools to study astrocytes in multiple sclerosis (MS). Tools available to study astrocyte heterogeneity (regional vs. functional). The RiboTag approach allows the analysis of messenger RNA (mRNA) expression using genetically defined samples. Single-cell RNA sequencing provides a method to identify new cell populations based on their unique transcriptional profiles. Assay for transposable accessible chromatin (ATAC)-seq enables the analysis of open chromatin through the addition of sequencing adaptors into accessible genomic regions. Immunophenotyping enables the analysis of astrocyte populations defined on the basis of surface molecule expression detectable by flow cytometry. HA, Hemagglutinin; IP, immunoprecipitation.
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