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Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis
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 inflammatio...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898969/ https://www.ncbi.nlm.nih.gov/pubmed/31810488 http://dx.doi.org/10.1186/s12974-019-1650-x |
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author | Magliozzi, Roberta Howell, Owain William Durrenberger, Pascal Aricò, Eleonora James, Rachel Cruciani, Carolina Reeves, Cheryl Roncaroli, Federico Nicholas, Richard Reynolds, Richard |
author_facet | Magliozzi, Roberta Howell, Owain William Durrenberger, Pascal Aricò, Eleonora James, Rachel Cruciani, Carolina Reeves, Cheryl Roncaroli, Federico Nicholas, Richard Reynolds, Richard |
author_sort | Magliozzi, Roberta |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6898969 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68989692019-12-11 Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis Magliozzi, Roberta Howell, Owain William Durrenberger, Pascal Aricò, Eleonora James, Rachel Cruciani, Carolina Reeves, Cheryl Roncaroli, Federico Nicholas, Richard Reynolds, Richard J Neuroinflammation Research 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. BioMed Central 2019-12-07 /pmc/articles/PMC6898969/ /pubmed/31810488 http://dx.doi.org/10.1186/s12974-019-1650-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Magliozzi, Roberta Howell, Owain William Durrenberger, Pascal Aricò, Eleonora James, Rachel Cruciani, Carolina Reeves, Cheryl Roncaroli, Federico Nicholas, Richard Reynolds, Richard Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis |
title | Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis |
title_full | Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis |
title_fullStr | Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis |
title_full_unstemmed | Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis |
title_short | Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis |
title_sort | meningeal inflammation changes the balance of tnf signalling in cortical grey matter in multiple sclerosis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898969/ https://www.ncbi.nlm.nih.gov/pubmed/31810488 http://dx.doi.org/10.1186/s12974-019-1650-x |
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