Astrocyte Crosstalk in CNS Inflammation

Abstract

Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated with specific genomic programs and functions. The advent of novel genomic technologies has enabled rapid progress in the characterization of astrocyte heterogeneity and its control by astrocyte interactions with other cells in the central nervous system (CNS). In this review, we provide an overview of the multifaceted roles of astrocytes in the context of CNS inflammation, highlighting recent discoveries on astrocyte subsets and their regulation. We explore mechanisms of crosstalk between astrocytes and other cells in the CNS in the context of neuroinflammation and neurodegeneration and discuss how these interactions shape pathological outcomes.

Keywords: astrocyte; cell interactions; glial cells; multiple sclerosis; neuroinflammation; trained immunity.

Figure 1.. Astrocyte signaling in the context of CNS inflammation.

The transcription factor NF-κB controls multiple aspects of astrocyte pro-inflammatory responses. NF-κB signaling is triggered/boosted by cytokines released by microglia and other cells in the inflamed CNS, and by the sphingolipids S1P and LacCer. AHR activation by dietary components, environmental factors or metabolites derived from the commensal flora limits NF-κB activation. Additional inflammatory pathways are triggered by the binding of environmental toxins to S1R/IRE1α and downstream signaling through XBP1.

Figure 2.. Astrocyte interactions in the context of neuroinflammation.

(A) Bidirectional communication between astrocytes and microglia regulates their responses during CNS inflammation. (B) Upon activation, astrocytes release neurotoxic amounts of NO, glutamate or downregulate the uptake of extracellular neurotransmitter, ultimately leading to neuronal and oligodendrocyte death. Astrocytes furthermore control the recruitment of oligodendrocytes through the secretion of multiple cytokines. In addition, astrocytes respond to pro-inflammatory mediators secreted by activated oligodendrocytes. (C) Astrocytes control the recruitment of leukocytes into perivascular spaces and the CNS parenchyma through the secretion of multiple molecules. Interactions between activated astrocytes and endothelial cells increase BBB permeability and facilitate leukocyte infiltration, while bidirectional communication between astrocytes and peripheral immune cells potentiates CNS inflammation and contributes to disease progression.

Figure 3.. Pro-inflammatory cytokine-induced epigenetic suppression of NRF2 signaling during CNS inflammation.

During initial exposure to inflammatory signals, astrocytes upregulate the formation of MAFG homodimers, which outcompete MAFG/NRF2 heterodimer binding to transcriptional response elements that control NRF2 signaling. In addition, MAT2α cooperates with MAFG and induces DNA methylation marks that restrict chromatin accessibility. Collectively, these epigenetic modifications suppress NRF2-driven inhibition of NF-κB signaling and lead to sustained inflammation.