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

Abstract

BackgroundRecent 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.MethodsTo 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.ResultsGene 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.ConclusionsWe 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.

B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis

“…We suggest that a higher level of demyelination and axonal loss in MS cases expressing meningeal lymphoid-like structures may in part be related to the increased immune cell infiltration in the cord meninges, which via the production of pro-inflammatory cytokines and chemokines, including TNF, IL6, IFNγ and CXCL13, could cause direct and/ or indirect damage to the underlying tissues (18,28,37,38). This inflammatory milieu is reflected in the CSF (27) and a small number of inflammatory mediators, including B cell chemokines, define both a post-mortem and a clinical cohort with a higher lesion load and poor prognosis (38).…”

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

“…First evidence of the involvement of TNF in the neuroinflammatory process occurring in MS were provided by post mortem studies in MS patients, showing high cytokine levels in close proximity to active CNS lesions [ 12 , 88 , 150 , 151 ]. Moreover, transcriptional analysis of cortical gray matter (GM) tissues of PMS subjects showed the upregulation of both TNFR1 and TNFR2 [ 152 ]. Further immunocytochemical characterizations have shown that TNFR1 is mainly expressed by neurons and oligodendrocytes, while TNFR2 is mostly expressed by microglia and astrocytes in cortical GM [ 152 ].…”

“…Moreover, transcriptional analysis of cortical gray matter (GM) tissues of PMS subjects showed the upregulation of both TNFR1 and TNFR2 [ 152 ]. Further immunocytochemical characterizations have shown that TNFR1 is mainly expressed by neurons and oligodendrocytes, while TNFR2 is mostly expressed by microglia and astrocytes in cortical GM [ 152 ]. However, the higher expression of genes linked to TNFR1-mediated necroptosis, a different form of necrotic cell death, suggested the prevalence of such TNF-mediated destructive pathway [ 152 ].…”

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

“…The understanding of such opposing effects of TNF on oligodendrocytes [ 14 ] has increased thanks to subsequent studies highlighting the dichotomy between solTNF and tmTNF and between their two TNF receptor subtypes. In particular, MS and EAE have been associated with harmful effects of solTNF via TNFR1 [ 163 , 164 , 165 ], while activation of oligodendroglial tmTNF/TNFR2 axis is capable to sustain oligodendrocyte maturation and remyelination [ 14 , 15 ] and to modulate the local inflammatory milieu by limiting detrimental microglial activation and immune cell infiltration from the blood circulation [ 166 ].…”