Glial Cells as Key Regulators in Neuroinflammatory Mechanisms Associated with Multiple Sclerosis

Abstract

Even though several highly effective treatments have been developed for multiple sclerosis (MS), the underlying pathological mechanisms and drivers of the disease have not been fully elucidated. In recent years, there has been a growing interest in studying neuroinflammation in the context of glial cell involvement as there is increasing evidence of their central role in disease progression. Although glial cell communication and proper function underlies brain homeostasis and maintenance, their multiple effects in an MS brain remain complex and controversial. In this review, we aim to provide an overview of the contribution of glial cells, oligodendrocytes, astrocytes, and microglia in the pathology of MS during both the activation and orchestration of inflammatory mechanisms, as well as of their synergistic effects during the repair and restoration of function. Additionally, we discuss how the understanding of glial cell involvement in MS may provide new therapeutic targets either to limit disease progression or to facilitate repair.

Keywords: astrocytes; blood–brain barrier; communication; demyelination; inflammation; microglia; neurodegeneration; oligodendrocytes; remyelination.

Figure 1

Glial cells populate lesions in a heterogeneous manner during the course of MS lesions. During the course of the disease, lesions change in respect to glial cell population. Active lesions contain macrophages at the center, while astrocytosis starts to be present. The rim of the lesion is populated with microglia which recruit other inflammatory cells to the site, as well as myelin-phagocytosing macrophages. Mixed active/inactive lesions do not show significant astrocyte population, while there is distinct formation of microglia around the rim. Additionally, there is recruitment of OPCs. Remyelination can be seen as a shadow plaque, where oligodendrocytes slowly initiate the repair process. Astrocytes and glial scar formation are clearly present at the center of the lesion. Inactive lesions show some degree of scar with few astrocytes and microglia present. Last but not least, recruitment of OPCs, and microglia nodules, can be seen in the NAWM, even in significant distance from the lesion site. OPC, Oligodendrocyte precursor cells; NAWM, normal-appearing white matter (figure was created with BioRender.com).

Figure 2

The role of oligodendrocytes in immunomodulation. In recent years, there has been increasing evidence of the role of oligodendrocyte in inflammatory activation. OPC proliferation is induced by IGF-2, VEGF-A, and TGF-β, while the presence of IL-1β, IL-17, and IFNγ has an inhibitory function. Nevertheless, the presence of OPCs further induced the recruitment of peripheral immune cells, modulation of other glial cells, as well as some degree of phagocytic activity. Mature myelinating oligodendrocytes may act as APCs, by expressing specific receptors like MHC-I and -II, as well as TLR3 and TNFR2. Most importantly, Cx47 expressed at the soma and proximal processes of the oligodendrocyte support intercellular communication. IGF-2, insulin-like growth factor; VEGF-A, Vascular endothelial growth factor; TGFβ, Transforming growth factor beta; IL-1β, Interleukin 1-beta; IL-17, Interleukin-17; IFNγ, Interferon-gamma; CCL2, C-C motif chemokine ligand 2; FGF, Fibroblast growth factor; TNFR2, Tumor necrosis factor receptor 2; TLR3, Toll-like receptor 3; Cx47, Connexin 47; MHC, Major histocompatibility complex; T reg, B reg, T and B regulatory cells; TCR, T cell receptor (figure was created with BioRender.com).

Figure 3

Glial cells in the center of inflammation and neurodegeneration in MS. During early MS, there is a significant compromise of the BBB, through which activated immune cells extravasate from the periphery into the CNS. Both astrocytes and microglia are activated into A1 and M1 states, respectively, and by secreting various pro-inflammatory molecules induce further in myelin destruction. Additionally, peripheral macrophages and microglia assist in myelin debris clearance. The activation of this proinflammatory state is devastating and determines the lesion formation. Later, both astrocytes and microglia shift their activation state into an anti-inflammatory, namely A2 and M2, respectively, whereby inducing scar formation and OPC recruitment, facilitate in myelin repair. Occasionally, there is activation back to the pro-inflammatory states, depending on environmental signals. IL-1α, Interleukin-1alpha; TNFα, Tumor necrosis factor alpha; C1q, Complement 1q; TGF-β, transforming growth factor-beta; IL-1β, Interleukin-1beta; CXCL10, C-X-C motif ligand 1; VEGF, Vascular endothelial growth factor; GM-CSF, Granulocyte-macrophage colony-stimulating factor; CCL2, C-C motif ligand 2; IL-6, Interleukin 6; IL-2, Interleukin 2; MΦ, Macrophage; ROS, Reactive oxygen species; NO, Nitric oxide; TNF, Tumor necrosis factor; IFNγ, Interferon gamma; FGF, Fibroblast growth factor; IL-10, Interleukin 10, IL-4, Interleukin-4; IGF-1, Insulin-like growth factor 1; IL-1β, Interleukin 1 beta; PDGF, Platelet derived growth factor; OPC, Oligodendrocyte precursor cell; IL-33, Interleukin 33 (figure was created with BioRender.com).