Protective Functions of Reactive Astrocytes Following Central Nervous System Insult.

Mathias Linnerbauer,Veit Rothhammer

doi:10.3389/fimmu.2020.573256

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.

Highlights

Astrocytes are the most abundant cell type in the mammalian central nervous system (CNS) and responsible for a multitude of functions
Aqp4 has been identified as a major target of autoantibodies in patients suffering from neuromyelitis optica (NMO), a rare CNS inflammatory disorder that has historically been closely associated to Multiple Sclerosis (MS) [35]
We will discuss astrocyte-derived mediators with anti-inflammatory or tissue-protective properties, and examine how these factors may guide future therapeutic strategies. In this context we will not focus on protective astrocyte functions mediated by inflammatory cytokines or cell-cell contact, which have been reviewed extensively elsewhere [49, 63, 64], but rather concentrate on soluble factors often overlooked in the field of neuroinflammation

Summary

INTRODUCTION

Astrocytes are the most abundant cell type in the mammalian central nervous system (CNS) and responsible for a multitude of functions. Aqp has been identified as a major target of autoantibodies in patients suffering from neuromyelitis optica (NMO), a rare CNS inflammatory disorder that has historically been closely associated to MS [35] In addition to their versatile functions in the steady-state, astrocytes sense and react to danger signals in a multistep process referred to as astrogliosis [36, 37]. Astrocytes themselves respond to myeloid-derived APRIL, another member of the TNF superfamily with an increase in IL-10 production, suppressing pro-inflammatory T-cell functions [57] These interactions between reactive astrocytes and cells of the adaptive immune system are complemented by their functions as part of the cerebral innate immune system [58]. In this context we will not focus on protective astrocyte functions mediated by inflammatory cytokines or cell-cell contact, which have been reviewed extensively elsewhere [49, 63, 64], but rather concentrate on soluble factors often overlooked in the field of neuroinflammation

PROTECTIVE EFFECTS OF REACTIVE ASTROCYTES FOLLOWING CNS INSULT

Neurotrophic Factors

Growth Factors and Neuropoietic Cytokines

THERAPEUTIC OUTLOOK AND DISCUSSION