The Role of Astrocytes in CNS Inflammation

Abstract

Astrocytes are the most abundant cell type in the central nervous system (CNS), performing complex functions in health and disease. It is now clear that multiple astrocyte subsets or activation states (plastic phenotypes driven by intrinsic and extrinsic cues) can be identified, associated to specific genomic programs and functions. The characterization of these subsets and the mechanisms that control them may provide unique insights into the pathogenesis of neurologic diseases, and identify potential targets for therapeutic intervention. In this article, we provide an overview of the role of astrocytes in CNS inflammation, highlighting recent discoveries on astrocyte subsets and the mechanisms that control them.

Keywords: astrocyte subsets; inflammation; reactive astrocytes.

Figure 1.. Reactive Astrocytes in Mouse and Humans in the Context of Central Nervous System (CNS) Viral Infection.

(A) Reactive astrocytes are induced in the context of viral infections through two major mechanisms: direct and indirect. The direct mechanism involves infection of astrocytes, which then become reactive astrocytes. Conversely, the indirect mechanism involves signaling molecules [e.g., interferon type I (IFN-I)] produced by neighboring infected cells (including other astrocytes as well as other cell types in the CNS). (B) Major signaling pathways involved in the generation of reactive astrocytes on viral infection. Double-stranded RNA (dsRNA), one of the major viral pathogen-associated molecular patterns (PAMPs), is recognized by the endosomal Toll-like receptor 3 (TLR3) as well as the cytoplasmic retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5), leading to the synthesis and release of IFN-I. Then, secreted IFN-Is activate autocrine and paracrine signaling cascades through the IFN-I receptor inducing the expression of IFN-stimulated genes (ISGs), mounting an effective antiviral response [–35]. AHR, aryl hydrocarbon receptor; IFNAR, interferon-α/β receptor; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; IRF9, interferon regulatory factor 9; MAVS, mitochondrial antiviral signaling protein; NF-κB, nuclear factor kappalight-chain-enhancer of activated B cells; SOCS2, suppressor of cytokine signaling 2; STAT, signal transducer and activator of transcription; TIPARP, TCDD inducible poly(ADP-ribose) polymerase; TRAF3, tumor necrosis factor receptorassociated factor 3. This figure was created using BioRender (https://biorender.com/).

Figure 2.. Metabolic Control of Mouse and Human Astrocytes.

Sphingolipid metabolism in astrocytes activates a novel signaling pathway involving cytosolic phospholipase A2 (cPLA2) and mitochondrial antiviral signaling protein (MAVS). Lactosylceramide (LacCer) produced by sphingolipid metabolism binds to and activates cPLA2, which then activates MAVS inducing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-driven proinflammatory transcriptional programs. MAVS activation also triggers metabolic remodeling that reduces lactate production and limits the metabolic support of neurons by astrocytes, boosting neurodegeneration [81]. B4GALT6, beta-1,4-galactosyltransferase 6; CCL2, chemokine (C-C motif) ligand 2; GM-CSF, granulocyte-macrophage colony-stimulating factor; NO, nitric oxide; TNF, tumor necrosis factor. This figure was created using BioRender (https://biorender.com/).

Figure 3.. Control of Mouse and Human Astrocytes by the Unfolded Protein Response (UPR) and Environmental Chemicals.

Platform for the unbiased identification of environmental factors that affect astrocyte responses. A small-molecule screen on a collection of environmental chemicals provided by the US Environmental Protection Agency (EPA) identified the herbicide linuron as an environmental chemical that increases inducible nitric oxide synthase (iNOS) expression in astrocyte-like cells in a novel zebrafish model of neurodegeneration; these findings were later validated in mouse and human astrocyte models. Computational modeling, genetic, and small-molecule perturbation studies on murine and human systems identified the mechanism of action of linuron, which activates the UPR via sigma non-opioid intracellular receptor 1 (SIGMAR1)–inositol-requiring enzyme 1 α (IRE1α)–X-box binding protein 1 (XBP1) signaling. UPR signaling is also activated and drives astrocyte proinflammatory programs even in the absence of linuron during experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) [93]. Csf2, colony-stimulating factor 2; ER, endoplasmic reticulum; Edem1, ER degradation-enhancing alpha-mannosidase-like protein 1; Nos2, nitric oxide synthase 2; XBP1s, X-box binding protein 1 spliced form; XBP1u, X-box binding protein 1 unspliced form. This figure was created using BioRender (https://biorender.com/).