Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

Abstract

Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic, and degenerative diseases such as Multiple Sclerosis, ischemic stroke, and Alzheimer's disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle yet untreatable disorders of the central nervous system.

Keywords: Alzheimer’s disease; astrocytes; astrogliosis; ischemic stroke; multiple sclerosis; neurodegeneration; neuroinflammation; protective.

Figure 1

Role of astrocytes in the steady state and inflammatory conditions. (A) Astrocytes interact with neurons, oligodendrocytes, microglia, and cells of the BBB during steady state conditions. (B) Astrocytes form tripartite synapses with neurons and regulate their synaptic transmission through metabolic support and the clearance of neurotransmitters. (C) Astrocytic endfeet line the cerebral vasculature and are a constituent of the blood brain barrier, thus limiting the infiltration of pathogens and peripheral immune cells into the central nervous system. Their endfeet express high levels of Aqp-4 and form a close interaction with pericytes and the basal lamina of the brain parenchyma. (D) During inflammatory conditions, reactive astrocyte secrete a plethora of inflammatory mediators that regulate functions of myeloid cells, lymphocytes, oligodendrocytes, neurons, and microglia. (E) Soluble inflammatory mediators derived from mircoglia and other immune cells differentially induce pathogenic (red) or protective (blue) astrocyte functions. (F) Peripheral immune cells pervade the BBB during inflammatory conditions and transgress into the CNS. C1q, Complement component 1q; IL-1β, Interleukin-1 β; IL-10, Interleukin 10; TNF-α, Tumor necrosis factor α; TGF-α, Transforming growth factor α; VEGF-B, Vascular endothelial growth factor B.

Figure 2

Anti-inflammatory and tissue-protective functions of reactive astrocytes. Activated astrocytes secrete soluble mediators with anti-inflammatory functions that help to resolve acute inflammation following CNS insult. NGF and TGF-β promote beneficial functions in microglia; LIF skews CD4 T-cells towards a regulatory phenotype; NGF promotes the differentiation into T_H2 cells; GDNF and CNDF have beneficial effects on blood brain barrier permeability. CNDF, MANF, and HB-EGF have been associated to anti-inflammatory functions on multiple cell types or cells that are not displayed. During later stages, astrocyte-derived mediators promote the survival of neurons and oligodendrocytes and aid the long-term regeneration following CNS insult. TGF-β, BDNF, FGF family members, DNF, CNTF, IGF-1, and LIF increase neuronal survival; CNTF, LIF, and PDGF family members promote oligodendrocyte differentiation and myelination. BDNF, Brain derived neurotrophic factor; CNTF, Ciliary neurotrophic factor; FGF, Fibroblast growth factor; GDNF, Glial cell line-derived neurotrophic factor; HB-EGF, Heparin-binding epidermal growth factor; IGF-1, Insulin-like growth factor 1; LIF, Leukemia inhibitory factor; MANF, Mesencephalic astrocyte-derived neurotrophic factor; NGF, Nerve growth factor; PDGF, Platelet-derived growth factor; T_H2, T helper type 2 cell; T_Reg, T regulatory cell; TGF-β, Transforming growth factor β.