Role of Microglia in Multiple Sclerosis

Introduction

Glial cells play many critical roles in the mediation of immune responses, transmission of axon potentials and maintenance of CNS (central nervous system) homeostasis. Demyelination refers to the loss of the myelin sheath, which affects the ability of the neurons to signal appropriately.

Demyelination can occur in the peripheral and central nervous system in response to viral infection, inflammatory disease or toxic insult. Table 1 shows several demyelinating diseases, of which multiple sclerosis or MS is perhaps the most well-known medical condition.

Despite the detailed description of the pathological and clinical features of multiple sclerosis, its etiology continues to be a mystery.

Table 1. Demyelinating diseases.

MS

Multiple sclerosis

ADEM

Acute-hemorrhagic leucoencephalitis

CCPD

Combined central and peripheral demyelination

Guillan-Barré Syndrome

Peripheral nerve demyelination

NMO

Neuromyelitis Optica

PML (Viral demyelination)

Progressive multifocal leukoencephalopathy

SSPE (Viral demyelination)

Subacute scerosing panencephalitis

 

The series of events leading to demyelination in the nervous system is vastly complex and is characterized by interactions between infiltrating and resident immune cells (usually auto-immune, Table 2), the glial cells containing nervous tissue and neurons.

Table 2. Autoantibodies in demyelination.

 

Neurofascin

CCPD

Guillan-Barré

MS

Experimental Autoimmune Encephalomyelitis (EAE)

Myelin components (gangliosides, glycoproteins etc.)

Guillan-Barré

EAE

MS

Aquaporin 4

NMO

 

When demyelination occurs, the myelin generated by oligodendrocytes is lost from around axons and apoptotic cell death of the oligodendrocyte may occur. This is accompanied by an influx of macrophages, T cells and B cells from the periphery along with the activation and proliferation of microglial cells residing in the CNS.

There is some evidence that, in demyelinating diseases, this inflammation is exacerbated by defects in, or damage to the blood-brain barrier (BBB). This highly impermeable barrier between CNS and blood is formed by endothelial cells. Research has demonstrated a reduced expression of the occludin and claudin-5 proteins at the BBB, while the ZO-1 is simultaneously relocated in this structure.

When microglial cells are activated, they become polarized into distinct phenotypes, of which M1 and M2 are the best described. M1 microglia, characterized by expression of pro-inflammatory molecules such as TNFα, iNOS, HLA-DR and TLRs and are found to occur early in demyelination.

They are very important in terms of antigen presentation, infiltrating macrophages from the periphery, phagocytosis of apoptotic cells and myelin debris, and in the generation of chemokine and cytokine profiles that help sustain a pro-inflammatory environment.

By contrast, M2 microglia are characterized by expression of TGFβ and Arg-1 molecules. They help promote regeneration and are likely to dominate at a later phase of the demyelination process. M2 microglia are involved in the recruitment of oligodendrocyte progenitors; matured oligodendrocyte progenitors remyelinate the denuded axons. Undoubtedly, the ratio of M2:M1 microglia is believed to be important in allowing an environment that is permissive for successful remyelination.

Another important player in the pathogenesis of demyelination is astrocytes. Since myelin is lost from the axon, glial fibrillary acidic protein (GFAP) is proliferated and upregulated by astrocytes through a process called "astrogliosis" – a hallmark of various CNS diseases.

Astrocytes have protective effects on neurons and also play a role in the maintenance of the BBB. These cells also perform many other different functions in the CNS, especially in inflammatory demyelination.

Astrocytes are similar to microglia and also express a wide range of inflammation-related molecules. They can execute antigen presentation and generate chemokine and cytokine profiles, which have intense effects on resident microglia and also on the infiltrating macrophages, B cells and T cells.

Just like microglia, these responses can either be inhibitory and pro-inflammatory for demyelination, or neuroprotective in that they can reduce the inflammation mediated by the T-cells and promote upregulation of neuroprotective molecules.

Suggested reading:

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Last updated: Jul 14, 2018 at 6:35 PM

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