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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Multiple Sclerosis | Research

Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis

Authors: Roberta Magliozzi, Owain William Howell, Pascal Durrenberger, Eleonora Aricò, Rachel James, Carolina Cruciani, Cheryl Reeves, Federico Roncaroli, Richard Nicholas, Richard Reynolds

Published in: Journal of Neuroinflammation | Issue 1/2019

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Abstract

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.
Appendix
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Metadata
Title
Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis
Authors
Roberta Magliozzi
Owain William Howell
Pascal Durrenberger
Eleonora Aricò
Rachel James
Carolina Cruciani
Cheryl Reeves
Federico Roncaroli
Richard Nicholas
Richard Reynolds
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1650-x

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