Glia maintain CNS homeostasis, support axonal signaling, and mediate immune responses. Demyelination, which describes the loss of the myelin sheath from around axons, impairs neuronal function and drives circuit dysfunction across a family of neurological conditions. This poster and its accompanying walkthrough trace the cellular glial cascade that unfolds during demyelination, applicable across MS and related conditions.

For the developmental biology of the glial populations discussed here, see Gliogenesis and myelination.

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The demyelinating disease family

Demyelination can occur in response to autoimmune disease, viral infection, or toxic insult. Multiple sclerosis (MS) is the most common example, but similar mechanisms operate across a broader family of conditions.

For a disease-focused resource on MS, see Multiple sclerosis.

For the MS-specific molecular and immunological cascade, see the multiple sclerosis pathway.

The demyelination pathway

The poster traces the cellular cascade from initial insult through attempted remyelination. The stages below follow that sequence.

1. BBB disruption and immune infiltration

Inflammatory, autoimmune, or toxic triggers compromise the blood–brain barrier (BBB). Decreased expression of tight junction proteins claudin-5 and occludin, alongside relocation of ZO-1, allows B cells, T cells, and macrophages to infiltrate the CNS, where they act alongside resident microglia. For a broader treatment of CNS immune activation, see neuroinflammation.

2. Oligodendrocyte injury and myelin loss

The immune assault converges on oligodendrocytes. Oligodendrocyte apoptosis and stripping of the myelin sheath expose axons, impairing saltatory conduction and initiating secondary axonal injury.

3. Microglial response

Microglia adopt a spectrum of functional states, historically framed as a pro-inflammatory to pro-repair dichotomy but now understood as a graded landscape. Early responses feature iNOS, TNFα, and MHC class II expression, supporting antigen presentation, phagocytosis of myelin debris, and cytokine-driven inflammation. Later responses, associated with Arg-1 and TGFβ, favor OPC recruitment and remyelination. For markers used to identify microglia and characterize their activation, see the microglia marker guide.

4. Astrocyte response

Astrocytes proliferate and upregulate GFAP in a process known as astrogliosis. They contribute inflammation-associated molecules, participate in antigen presentation, and produce cytokine and chemokine signals that can either amplify inflammation or promote neuroprotection, depending on context. For markers used to characterize astrocytes, see the astrocyte marker guide.

5. Attempted remyelination

Recruited oligodendrocyte precursor cells (OPCs) proliferate and migrate to lesions, where they can differentiate into new myelinating oligodendrocytes. In chronic demyelinating disease, this repair is often incomplete: differentiation into mature oligodendrocytes is blocked by the hostile lesion environment, making failed terminal differentiation a central bottleneck in remyelination. For markers used to identify OPCs and mature oligodendrocytes, see the oligodendrocyte marker guide.

Related pages

References

1. Franklin RJM, Ffrench-Constant C. Regenerating CNS myelin — from mechanisms to experimental medicines. Nat Rev Neurosci. 2017;18(12):753–769.
2. Paolicelli RC, Sierra A, Stevens B, et al. Microglia states and nomenclature: a field at its crossroads. Neuron. 2022;110(21):3458–3483.
3. Kuhlmann T, Ludwin S, Prat A, et al. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133(1):13–24.