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Reactive microglia in dysmyelination and demyelination
S C Zhang1, B D Goetz, J L Carré
1Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706-1102, USA. zhangs@svm.vetmed.wisc.edu
Abstract:
The relationship between microglial activation and dysmyelination/demyelination was analyzed in a long-lived myelin mutant, the Long Evans shaker (les) rat, which exhibits early dysmyelination and a later loss of abnormal myelin sheaths. A microglial reaction characterized by progressive morphological transformation and increasing cell density was localized exclusively to white matter during postnatal 2-4 weeks, suggesting a microglial response to dysmyelination and oligodendroglial pathology. A further microglial reaction as marked by microglial expression of MHC II and a concomitant expression in the brain and spinal cord of mRNA for interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) began around 4 weeks when the remaining myelin was lost. Ultrastructurally, activated microglia ingested numerous myelin figures, suggestive of active phagocytosis. Thus, this study indicates that microglial reaction is graded in chronic neurological disorders and suggests that MHC II expression marks a functional change of activated microglia.
Insights
Microglia activation correlates with myelin damage in the Long Evans shaker rat model. This study shows microglia respond to and clear myelin debris in chronic neurological disorders.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- The Long Evans shaker (les) rat is a valuable model for studying myelin disorders due to its progressive dysmyelination and demyelination.
- Microglia, the resident immune cells of the central nervous system, are known to respond to neuronal injury and inflammation.
Purpose of the Study:
- To investigate the relationship between microglial activation and myelin pathology in the les rat model.
- To characterize the temporal and functional changes in microglia during chronic demyelination.
Main Methods:
- Analysis of microglial morphology and density in the white matter of les rats during postnatal development.
- Assessment of microglial expression of MHC II, IL-1 beta, TNF-alpha, and iNOS mRNA in the brain and spinal cord.
- Ultrastructural examination of microglia to identify phagocytic activity.
Main Results:
- Microglial activation, marked by morphological changes and increased cell density, was observed in white matter from postnatal weeks 2-4, coinciding with early dysmyelination.
- A heightened microglial response, including MHC II expression and increased pro-inflammatory cytokine mRNA (IL-1 beta, TNF-alpha, iNOS), occurred around 4 weeks as myelin was lost.
- Ultrastructural analysis revealed microglia actively phagocytosing myelin debris.
Conclusions:
- Microglial reaction in chronic neurological disorders is a graded process, intensifying as demyelination progresses.
- MHC II expression serves as a marker for a functional shift in activated microglia, indicating active phagocytosis and immune response.
- The findings highlight the critical role of microglia in responding to and clearing myelin pathology in demyelinating diseases.