The Role of Astrocytes in Multiple Sclerosis Progression

Abstract

Multiple sclerosis (MS) is an inflammatory disorder causing central nervous system (CNS) demyelination and axonal injury. Although its etiology remains elusive, several lines of evidence support the concept that autoimmunity plays a major role in disease pathogenesis. The course of MS is highly variable; nevertheless, the majority of patients initially present a relapsing-remitting clinical course. After 10-15 years of disease, this pattern becomes progressive in up to 50% of untreated patients, during which time clinical symptoms slowly cause constant deterioration over a period of many years. In about 15% of MS patients, however, disease progression is relentless from disease onset. Published evidence supports the concept that progressive MS reflects a poorly understood mechanism of insidious axonal degeneration and neuronal loss. Recently, the type of microglial cell and of astrocyte activation and proliferation observed has suggested contribution of resident CNS cells may play a critical role in disease progression. Astrocytes could contribute to this process through several mechanisms: (a) as part of the innate immune system, (b) as a source of cytotoxic factors, (c) inhibiting remyelination and axonal regeneration by forming a glial scar, and (d) contributing to axonal mitochondrial dysfunction. Furthermore, regulatory mechanisms mediated by astrocytes can be affected by aging. Notably, astrocytes might also limit the detrimental effects of pro-inflammatory factors, while providing support and protection for oligodendrocytes and neurons. Because of the dichotomy observed in astrocytic effects, the design of therapeutic strategies targeting astrocytes becomes a challenging endeavor. Better knowledge of molecular and functional properties of astrocytes, therefore, should promote understanding of their specific role in MS pathophysiology, and consequently lead to development of novel and more successful therapeutic approaches.

Keywords: astrocytes; axon; glial scar; microglia; mitochondria; multiple sclerosis; multiple sclerosis progression; myelin.

Figure 1

Main mechanisms involved in neurodegeneration driven by astrocytes. Several studies have demonstrated diverse roles of astrocytes in lesion development during the course of MS. Activation of astrocytes and loss of end-feet around small vessels are early events in lesion development, associated to loss of BBB function and consequently to CNS inflammation (1). Astrocytes mediate innate immune responses through several mechanisms. They modulate cell entry into the CNS by regulating adhesion molecule expression profiles, particularly of VCAM-1 and ICAM-1 (1). Astrocytes may also affect the number and phenotype of T cells in the CNS, committing T cells to a pro-inflammatory or regulatory phenotype. By contrast, astrocytes may also terminate T cell response, either by induction of apoptosis, or induction of Galectin-9. Furthermore, production of IL-15 or of BAFF drives immune responses mediated by cytotoxic CD8⁺ T cells or by B cells (2). Activated astrocytes secrete different chemokines, which attract both peripheral immune cells and microglia to MS lesions (2, 3). In the EAE model, astrocytes produce LacCer during the chronic phase, leading to induction of GM-CSF and CCL2 genes, and to subsequent microglial activation and monocyte infiltration (4). In areas of myelin breakdown, it has been documented that astrocytes secrete compounds with toxic effects for neurons, axons, and oligodendrocytes (5), reduce glutamate uptake by astrocyte transporters (6), and increase expression of purinergic receptors (7). These factors contribute to loss of glutamate buffering capacity mediated by astrocytes, mitochondrial dysfunction, energy deficiency, accumulation of intra-axonal Ca²⁺, and subsequent activation of proteolitic enzymes (9). Astrocytes respond to injuries by forming a glial scar that inhibits remyelination and axonal regeneration. These effects are mediated through secretion of fibroblast growth factor-2 (FGF-2) and of inhibitory extracellular matrix (ECM) molecules, such as condroitin sulfate proteoglycans (CSPGs) and Ephrins (8). Old age adversely affects astrocyte viability and self-renewal capacity, resulting in the generation of senescent and/or dysfunctional cells, evidenced in the form of cell fragmentation (10). Senescent astrocytes appear to be in a state of chronic activation, associated with pro-inflammatory cytokine and prostaglandins secretion.