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Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis
Roberta Magliozzi1,2, Owain William Howell3,4, Pascal Durrenberger3
1Department of Brain Sciences, Department of Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Imperial College London, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK. rmagliozzi73@gmail.com.
Background:
Recent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases.
Methods:
To investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls.
Results:
Gene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia.
Conclusions:
We suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of TNF signalling.
Insights
Meningeal inflammation in multiple sclerosis (MS) alters tumor necrosis factor (TNF) signaling in the brain, promoting grey matter damage and neurodegeneration. This highlights a key pathway driving MS pathology.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Cortical pathology in secondary progressive multiple sclerosis (MS) is linked to meningeal inflammation and grey matter lesions.
- Meningeal inflammation involves lymphoid-like structures and significant neuronal/glial loss.
Purpose of the Study:
- To investigate molecular changes in the motor cortex due to meningeal inflammation in MS.
- To understand the consequences of pro-inflammatory molecules from the meninges on grey matter.
Main Methods:
- Gene expression profiling of motor cortex from 20 MS brains and 10 controls.
- Analysis of brains with and without substantial meningeal inflammation.
- RT-PCR confirmation of gene expression changes.
Main Results:
- MS brains showed significant pathological cell changes, exacerbated by meningeal inflammation.
- Genes in tumor necrosis factor (TNF) signaling pathways were deregulated in MS.
- Increased meningeal inflammation shifted TNF signaling towards pro-apoptotic pathways in grey matter.
Conclusions:
- Meningeal inflammation in MS generates an inflammatory environment affecting the subarachnoid space.
- This inflammatory milieu drives demyelination and neurodegeneration in the underlying grey matter.
- Altered TNF signaling balance is a key mechanism mediating grey matter pathology in MS.
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