Abstract
In multiple sclerosis (MS), astrocytes respond to the inflammatory stimulation with an early robust process of morphological, transcriptional, biochemical, and functional remodeling. Recent studies utilizing novel technologies in samples from MS patients, and in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), exposed the detrimental and the beneficial, in part contradictory, functions of this heterogeneous cell population. In this review, we summarize the various roles of astrocytes in recruiting immune cells to lesion sites, engendering the inflammatory loop, and inflicting tissue damage. The roles of astrocytes in suppressing excessive inflammation and promoting neuroprotection and repair processes is also discussed. The pivotal roles played by astrocytes make them an attractive therapeutic target. Improved understanding of astrocyte function and diversity, and the mechanisms by which they are regulated may lead to the development of novel approaches to selectively block astrocytic detrimental responses and/or enhance their protective properties.
Highlights
Essential data on multiple sclerosis (MS) have been obtained using an animal model, experimental autoimmune encephalomyelitis (EAE), induced by injection of myelin antigens such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), or myelin proteolipid protein (PLP), emulsified in enriched adjuvant, accompanied by administration of pertussis toxin [4,8]. This leads to the priming of myelin-specific T-cells in peripheral lymphoid organs, their differentiation into effector T-cells and their entry into the central nervous system (CNS), where they are reactivated via interaction with specific myelin antigens on local antigen-presenting cells (APCs)
Additional factors released by reactive astrocytes that were shown to interfere with oligodendrocyte progenitor cells (OPCs) differentiation are fibroblast growth factor-2 (FGF-2) [119] and cytokines, such as tumor necrosis factor (TNF)-α, and IL-6 [120,121]
While the pathological inflammatory process in MS/EAE is primarily initiated by bone-marrow-derived components, it is currently clear that astrocytes play essential roles in recruiting, instructing, and retaining these leukocytes at the lesion sites, engendering the positive-feedback inflammatory loop that mediates the disease
Summary
Essential data on MS have been obtained using an animal model, experimental autoimmune encephalomyelitis (EAE), induced by injection of myelin antigens such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), or myelin proteolipid protein (PLP), emulsified in enriched adjuvant, accompanied by administration of pertussis toxin [4,8]. This leads to the priming of myelin-specific T-cells in peripheral lymphoid organs, their differentiation into effector T-cells (mostly Th1 and Th17) and their entry into the CNS, where they are reactivated via interaction with specific myelin antigens on local antigen-presenting cells (APCs). The various EAE models have been highly valuable for studying the pathological mechanisms involved in MS, as well as for drug development
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