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Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis
Owain W Howell1, Jon L Rundle1, Anurag Garg1
1Centre for Neuroscience, Division of Experimental Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London W12 0NN.
Abstract:
The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. We describe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent of paranodal axoglial (neurofascin-155(+)/Caspr1(+)) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction.
Insights
Microglial activation in normal-appearing white matter (NAWM) is linked to axonal injury in multiple sclerosis (MS). This disruption of the axoglial unit in MS NAWM is an early sign of axonal damage.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Chronic multiple sclerosis (MS) exhibits complex symptoms partly due to widespread axonal abnormalities in both lesional and nonlesional central nervous system areas.
- Microglial activation is increasingly recognized as a key factor in neurodegenerative processes.
Purpose of the Study:
- To investigate the association between microglial activation and axonal/oligodendrocyte pathology in normal-appearing white matter (NAWM) in MS.
- To explore the role of axoglial disruption in early axonal injury and its potential reversibility.
Main Methods:
- Analysis of MS cases and experimental autoimmune encephalomyelitis (EAE) models to examine microglial activation and axoglial integrity (neurofascin-155/Caspr1).
- Assessment of axonal injury markers (nonphosphorylated neurofilaments) and correlation with microglial inflammation and lymphocyte density.
- Investigation of axoglial unit integrity in Parkinson disease cases and preclinical/chronic EAE models.
- Evaluation of minocycline's effect on microglial activation and axoglial integrity in actively immunized animals.
Main Results:
- Paranodal axoglial disruption in MS NAWM correlated with local microglial inflammation and axonal injury, independent of demyelinating lesions or lymphocyte density.
- Similar axoglial alterations were observed in Parkinson disease and preclinical EAE, preceding immune cell infiltration.
- Axoglial disruption was reversible in early EAE with resolving microglial inflammation but persisted in chronic EAE.
- Minocycline treatment preserved axoglial integrity by inhibiting microglial activation in actively immunized animals.
Conclusions:
- Permanent disruption of axoglial domains in MS NAWM, driven by microglial inflammation, is an early indicator of axonal injury.
- This early axonal injury likely impairs nerve conduction and contributes to the physiological dysfunction seen in MS.
- Targeting microglial activation may offer a therapeutic strategy to preserve axoglial integrity and prevent axonal damage in MS.
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