Journal Article

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

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

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Apoptosis / Astrocytes / Autopsy / Biomedical and Life Sciences / Biomedicine / Brain / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Chronic illnesses / Cortex (motor) / Cortical grey matter lesion / Cytotoxicity / Demyelination / Development and progression / Dissection / Female / Gene expression / Genomes / Gray Matter - metabolism / Gray Matter - pathology / Humans / Immunology / Inflammation / Inflammation - genetics / Inflammation - metabolism / Inflammation - pathology / Male / Medical research / Medicine, Experimental / Meningeal inflammation / Meninges / Meninges - metabolism / Meninges - pathology / Microglia / Middle Aged / Multiple sclerosis / Multiple Sclerosis - genetics / Multiple Sclerosis - metabolism / Multiple Sclerosis - pathology / Necroptosis / Neurobiology / Neurodegeneration / Neurology / Neuronal-glial interactions / Neuropathology / Neurosciences / NF-κB protein / NMR / Nuclear magnetic resonance / Oligodendrocytes / Pathology / Polymerase chain reaction / Signal transduction / Signal Transduction - physiology / Subarachnoid space / Substantia grisea / TNF / Transcriptome - physiology / Tumor necrosis factor / Tumor necrosis factor receptors / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - metabolism / Tumors