Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration
| Autor: | Richard Reynolds, Rachel E. James, Ioanna Eleftheriadou, Carmen Picon Munoz, Nicholas D. Mazarakis, Renee Schalks, Eleanor Browne |
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| Přispěvatelé: | Multiple Sclerosis Society, National Multiple Sclerosis Society, Lee Kong Chian School of Medicine (LKCMedicine), Centre for Molecular Neuropathology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Multiple Sclerosis
Encephalomyelitis Autoimmune Experimental Necroptosis Inflammation 0601 Biochemistry and Cell Biology lcsh:RC346-429 Pathology and Forensic Medicine Proinflammatory cytokine Myelin oligodendrocyte glycoprotein Multiple sclerosis Interferon-gamma Cellular and Molecular Neuroscience Meninges medicine Animals Humans Medicine [Science] Animal model Neurodegeneration lcsh:Neurology. Diseases of the nervous system Cerebral Cortex biology Tumor Necrosis Factor-alpha Research 1103 Clinical Sciences medicine.disease Rats medicine.anatomical_structure Nerve Degeneration Immunology biology.protein Cytokines Tumor necrosis factor alpha Neurology (clinical) medicine.symptom Demyelination 1109 Neurosciences Demyelinating Diseases |
| Zdroj: | Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-18 (2020) Acta Neuropathologica Communications |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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