Abstract
Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.
Highlights
Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis
It is important to note that while the immune system plays an important role in mediating the clinical exacerbations among patients with relapsing-remitting Multiple sclerosis (MS) (RR-MS), disease progression is not modified by current immunomodulatory therapies and indicates that key aspects of disease pathogenesis are independent of autoimmunity [3]
In the naive CNS, astrocytes can be broadly categorized into five distinct types based on their anatomical locations: (1) white matter astrocytes, which have numerous fine membranous projections giving them a star-like appearance; (2) gray matter astrocytes, which have a less complex shape and are often referred to as “protoplasmic”, (3) ependymal astrocytes, which are glial fibrillary acidic protein (GFAP)+ cells found within the stem cell niches of the brain that may be a form of progenitor cell; (4) radial glia found within the deep layers of the cerebral cortex that send projections toward the pial membrane and provide a scaffold for migrating neurons during brain development, and (5) perivascular astrocytes, which are GFAP+ cells with specialized projections called “vascular feet” that surround the neurovasculature
Summary
Multiple sclerosis (MS) is the most common demyelinating disease of the CNS [1]. It is the most common neurological disease among young adults affecting approximately 2.5 million people worldwide [2]. (3) ependymal astrocytes, which are GFAP+ cells found within the stem cell niches of the brain that may be a form of progenitor cell; (4) radial glia found within the deep layers of the cerebral cortex that send projections toward the pial membrane and provide a scaffold for migrating neurons during brain development, and (5) perivascular astrocytes, which are GFAP+ cells with specialized projections called “vascular feet” that surround the neurovasculature Recognized for their diverse functions in CNS homeostasis, astrocytes can serve many functions including acting as guards to CNS injury and inflammation.
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