Extensive subpial cortical demyelination is specific to multiple sclerosis

Junker, Andreas; Wozniak, Jadwiga; Voigt, David; Scheidt, Uta; Antel, Jack; Wegner, Christiane; Brück, Wolfgang; Stadelmann, Christine

doi:10.1111/bpa.12813

Cited by 56 publications

(39 citation statements)

References 77 publications

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“…Oxidative injury is a pathologic feature linked to neurodegeneration, myelin damage and disease progression in MS and other neurodegenerative diseases 1 – 7 . Oxidative stress mediated by reactive oxygen species (ROS) release from CNS innate immune cells promotes neurodegeneration and demyelination 1 , 3 , 8 – 10 .…”

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confidence: 99%

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

et al. 2020

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Oxidative stress is a central part of innate-immune induced neurodegeneration. However, the transcriptomic landscape of the central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease, and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells (Tox-seq) identified a core oxidative stress gene signature coupled to coagulation and glutathione pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen (HTS) and oxidative stress gene network analysis, identified the glutathione regulating compound acivicin with potent therapeutic effects decreasing oxidative stress and axonal damage in chronic and relapsing multiple sclerosis (MS) models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable the discovery of selective neuroprotective strategies.

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confidence: 99%

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

et al. 2020

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“…It is also not known whether necroptotic neuron death occurs in other CNS inflammatory conditions in which one might expect levels of TNF to be increased in the CNS. Although subpial demyelination appears to be specific to MS [9,22], comparable studies on the role of cytokine-induced neuronal loss in the upper cortical layers in non-MS neuroinflammatory disorders with similar long disease duration have yet to be carried out.…”

Section: Discussionmentioning

confidence: 99%

Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

et al. 2021

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Sustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

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“…Whilst an anti-MOG response and involvement of the complement system [39] may increase the speed and severity of MS-like pathology, indicated by the more extensive demyelination in MOG immunised animals, it does not appear to be necessary for the development of chronic meningeal inflammation and accumulating neuronal loss, which were not significantly different between the two animal groups. In this respect it is of interest to note that non-MS inflammatory CNS conditions that are accompanied by meningeal inflammation, such as viral meningitis and tuberculosis meningitis, are not characterised by extensive subpial demyelination [13,19,22], despite the likely presence of elevated proinflammatory cytokines in the CSF. This points towards an MS-specific mechanism underlying the subpial demyelination, which agrees with the finding that an antimyelin immune response is necessary for very extensive demyelination in our current model.…”

Section: Discussionmentioning

confidence: 99%

Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration

James

Schalks

Browne

et al. 2020

acta neuropathol commun

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Analysis of isolated meninges and cerebrospinal fluid (CSF) of post-mortem MS cases has shown increased gene and protein expression for the pro-inflammatory cytokines: tumour necrosis factor (TNF) and interferon-γ (IFNγ). Here we tested the hypothesis that persistent production of these cytokines in the meningeal compartment and diffusion into underlying GM can drive chronic MS-like GM pathology. Lentiviral transfer vectors were injected into the sagittal sulcus of DA rats to deliver continuous expression of TNF + IFNγ transgenes in the meninges and the resulting neuropathology analysed after 1 and 2 months. Injection of TNF + IFNγ viral vectors, with or without prior MOG immunisation, induced extensive immune cell infiltration (CD4+ and CD8+ T-cells, CD79a + B-cells and macrophages) in the meninges by 28 dpi, which remained at 2 months. Control GFP viral vector did not induce infiltration. Subpial demyelination was seen underlying these infiltrates, which was partly dependant on prior myelin oligodendrocyte glycoprotein (MOG) immunisation. A significant decrease in neuronal numbers was seen at 28 and 56 days in cortical layers II-V that was independent of MOG immunisation. RNA analysis at 28 dpi showed an increase in expression of necroptotic pathway genes, including RIP3, MLKL, cIAP2 and Nox2. PhosphoRIP3+ and phosphoMLKL+ neurons were present in TNF + IFNγ vector injected animals, indicating activation of necroptosis. Our results suggest that persistent expression of TNF in the presence of IFNγ is a potent inducer of meningeal inflammation and can activate TNF signalling pathways in cortical cells leading to neuronal death and subpial demyelination and thus may contribute to clinical progression in MS.

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Extensive subpial cortical demyelination is specific to multiple sclerosis

Cited by 56 publications

References 77 publications

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration

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