The role of glia in demyelinating diseases

Glia play crucial roles in the maintenance of CNS homeostasis, transmission of axon potentials and mediation of immune responses. Demyelination is the loss of the myelin sheath, which leads to inability of neurons to signal properly.

Download a pdf copy of the 'glia and demyelinating diseases' poster

​​Demyelination in the central and peripheral nervous system can occur in response to inflammatory disease, viral infection or toxic insult. There are a number of demyelinating diseases (see Table 1 below), of which multiple sclerosis (MS) is probably the most well-known. Although the clinical and pathological features of multiple sclerosis have been described in detail there still remains much mystery about its etiology.  

Table 1: Demyelinating diseases
MSMultiple sclerosis
ADEMAcute-hemorrhagic leucoencephalitis
CCPDCombined central & peripheral demyelination
Guillan-Barré​ SyndromePeripheral nerve demyelination
NMONeuromyelitis Optica
PML (Viral demyelination)Progressive multifocal leukoencephalopathy
SSPE (Viral demyelination)Subacute scerosing panencephalitis


The sequence of events leading to demyelination in the nervous system is vastly complex and involves the interaction between resident and infiltrating immune cells (often auto-immune, see Table 2 below), neurons and the glial cells comprising nervous tissue.​​​

Table 2: Autoantibodies in demyelination





Experimental Autoimmune Encephalomyelitis (EAE)

Myelin components (gangliosides, glycoproteins etc.)




Aquaporin 4NMO

​​​​At the onset of demyelination, myelin produced by oligodendrocytes is lost from around axons and apoptotic cell death of the oligodendrocyte may occur. There is a concomitant influx of B cells, T cells and macrophages from the periphery, as well as activation and proliferation of resident microglial cells 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. Studies have shown decreased expression of the proteins claudin-5 and occludin at the BBB, with a simultaneous relocation of ZO-1 in this structure.

When activated, microglia can become polarized into distinct phenotypes, the best described of which are M1 and M2. M1 microglia, characterized by expression of pro-inflammatory molecules such as iNOS, TNFα, TLRs and HLA-DR, are found to be present early in demyelination. They are very important, along with infiltrating macrophages from the periphery, in antigen presentation, phagocytosis of myelin debris and apoptotic cells and in production of chemokines and cytokines that help maintain a pro-inflammatory environment.

M2 microglia on the other hand are characterized by expression of molecules such as Arg-1 and TGFβ​, tend to dominate at a later stage of the demyelination process and help promote regeneration. They are known to be involved in the recruitment of oligodendrocyte progenitors which, on maturation, can remyelinate denuded axons. Indeed, it is thought that the ratio of M2:M1 microglia may be critical in allowing an environment that is permissive for successful remyelination.

Astrocytes are also critical players in the pathogenesis of demyelination. As myelin is lost from the axon, astrocytes proliferate and upregulate glial fibrillary acidic protein (GFAP) in a process known as "astrogliosis", a hallmark of many CNS diseases. Although known for their protective effects on neurons and their role in maintenance of the BBB, astrocytes carry out numerous other functions in the CNS, particularly in inflammatory demyelination.

Like microglia, astrocytes also express a wide variety of inflammation-associated molecules, are capable of antigen presentation and produce cytokine and chemokine profiles which have profound effects both on resident microglia and infiltrating T cells, B cells and macrophages. As with microglia, these responses can be pro-inflammatory and inhibitory for demyelination or may be neuroprotective, in that they can limit T-cell mediated inflammation and cause upregulation of neuroprotective molecules.

Suggested reading

  • Barnett SC, Linnington C, 2013. Myelination: do astrocytes play a role? ​Neurosci,​ 19, 442-450.

  • Barres BA, 2008. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron, 60, 430-440.
  • Blackburn D, Sargsyan S, Monk PN, Shaw PJ, 2009. Astrocyte function and role in motor neuron disease: a future therapeutic target? Glia, 57, 1251-1264.
  • Bomprezzi R, Campagnolo D, 2009. Inflammatory Demyelinating Diesease of the Central. Barrow Q. 24.
  • Brosnan CF, Raine CS, 2013. The astrocyte in multiple sclerosis revisited. Glia, 61, 453-465.
  • Carpentier PA, Duncan DS, Miller DS, 2008. Abcam poster TLR br inf autoimm Carpentier 2008 Br Behav Imm.pdf. Brain Behav Immun​, 22, 140-147.
  • Claycomb KI, Johnson KM, Winokur PN, Sacino AV, Crocker SJ, 2013. Astrocyte regulation of CNS inflammation and remyelination. Brain Sci, 3, 1109-1127.
  • Goldenburg MM, 2012. Multiple sclerosis review. PT, 37, 175-184.
  • Gudi V, Gingele S, Skripuletz T, Stangel M, 2014. Glial response during cuprizone-induced de- and remyelination in the CNS: Lessons learned. Front Cell Neurosci, 8, 73.
  • Kipp M, van der Star BJ, Vogel DYS, Puentes F, van der​ Valk P, Baker D, Amor S, 2012. Experimental in vivo and in vitro models of multiple sclerosis: EAE and beyond. Mult Scler Relat Disord, 1, 15-28.
  • Love S, 2006. Demyelinating diseases. J Clin Pathol, 59, 1151-1159.
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  • Montgomery DL, 1994. Astrocytes: Form, Functions, and Roles in Disease. Vet Pathol​, 31, 145-167.
  • Nair A, Frederick, TJ, Miller SD, 2008. Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci​, 65, 2702-2720.
  • Napoli I, Neumann H, 2010. Protective effects of microglia in multiple sclerosis. Exp Neurol​, 225, 24-28.
  • Popescu BFG, Lucchinetti CF, 2012. Pathology of demyelinating diseases. Annu Rev Pathol, 7, 185-217.
  • Ridet JL, Malhotra SK, Privat A, Gage FH, 1997. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci, 20, 570-577.
  • Saijo K, Glass CK, 2011. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol, 11, 775-787.
  • Saikali P, Cayrol R, Vincent T, 2009. Anti-aquaporin-4 auto-antibodies orchestrate the pathogenesis in neuromyelitis optica. Autoimmun Rev, 9, 132-135.
  • Sharma R, Fischer MT, Bauer J, Felts PA, Smith KJ, Misu T, Fujihara K, Bradl M, Lassmann H, 2010. Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination. Acta Neuropathol​, 120, 223-326.
  • Sheikh AM, Nagai A, Ryu JK, McLarnon JG, Kim SU, Masuda J, 2009. Lysophosphatidylcholine induces glial cells activation: role of rho kinase. Glia, 57, 898-907.
  • Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E, Berger K, Kipp M, Baumgä​rter W, Stangel M, 2013. Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain, 136, 147-167.
  • Vincent T, Saikali P, Cayrol R, Roth AD, Bar-Or A, Prat A, Antel JP, 2008. Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment.

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