Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis.
Roberta Magliozzi,Roberta Magliozzi,Owain W. Howell,Owain W. Howell,Pascal F. Durrenberger,Eleonora Aricò,Rachel James,Carolina Cruciani,Cheryl Reeves,Federico Roncaroli,Richard Nicholas,Richard Reynolds +11 more
Reads0
Chats0
TLDR
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.Abstract:
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. 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. 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. 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.read more
Citations
More filters
Journal ArticleDOI
The potential of serum neurofilament as biomarker for multiple sclerosis.
TL;DR: In this paper, the authors proposed specific clinical scenarios where implementing sNfL measures may be of utility, including, among others, initial diagnosis, first treatment choice, surveillance of subclinical disease activity and guidance of therapy selection.
Journal ArticleDOI
B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis
Camilla Reali,Camilla Reali,Roberta Magliozzi,Roberta Magliozzi,Federico Roncaroli,Federico Roncaroli,Federico Roncaroli,Richard Nicholas,Owain W. Howell,Owain W. Howell,Richard Reynolds +10 more
TL;DR: It is shown that the presence of lymphoid‐like structures in the forebrain is associated with a profound spinal cord pathology and local B cell rich meningeal inflammation associates with the extent of cord pathology, which supports a principal role for B cells in sustaining inflammation and tissue injury throughout the CNS in the progressive disease stage.
Journal ArticleDOI
A decade of cell death studies: Breathing new life into necroptosis.
TL;DR: This review focuses on programmed cell necrosis (i.e., necroptosis) as a promising research direction that will help in understanding the molecular and cellular processes behind different pathological conditions, such as chronic inflammation, neurodegeneration, and cardiovascular diseases.
Journal ArticleDOI
TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus.
Anusha Jayaraman,Thein Than Htike,Rachel James,Carmen Picón,Richard Reynolds,Richard Reynolds +5 more
TL;DR: In this paper, the authors demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons.
Journal ArticleDOI
Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter
Carmen Picón,Anusha Jayaraman,Rachel James,Catriona Beck,Patricia Gallego,Maarten E. Witte,Jack van Horssen,Nicholas D. Mazarakis,Richard Reynolds,Richard Reynolds +9 more
TL;DR: Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, this article showed an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis.
References
More filters
Journal ArticleDOI
Cortical demyelination and diffuse white matter injury in multiple sclerosis
Alexandra Kutzelnigg,Claudia F. Lucchinetti,Christine Stadelmann,Wolfgang Brück,Helmut Rauschka,Markus Bergmann,Manfred Schmidbauer,Joseph E. Parisi,Hans Lassmann +8 more
TL;DR: Global brain pathology in multiple sclerosis is analysed, focusing on the normal-appearing white matter (NAWM) and the cortex, to suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter.
Journal ArticleDOI
Immunopathology of multiple sclerosis
TL;DR: The current understanding of multiple sclerosis immunopathology is discussed, long-standing hypotheses regarding the role of the immune system in the disease are evaluated, and key questions that are still unanswered are delineated.
Journal ArticleDOI
Necroptosis and its role in inflammation
TL;DR: The mechanisms regulating necroptosis and its potential role in inflammation and disease are discussed and RIPK1 has important kinase-dependent and scaffolding functions that inhibit or trigger necroPTosis and apoptosis.
Journal ArticleDOI
Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.
TL;DR: The hypothesis that demyelination, axonal transection, dendritic tran section, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients is supported.
Journal ArticleDOI
The relation between inflammation and neurodegeneration in multiple sclerosis brains
Josa M. Frischer,Stephan Bramow,Assunta Dal-Bianco,Claudia F. Lucchinetti,Helmut Rauschka,Manfred Schmidbauer,Henning Laursen,Per Soelberg Sørensen,Hans Lassmann +8 more
TL;DR: It is found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease, and the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.