Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment
The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an infla...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/65469 |
| _version_ | 1811180480695894016 |
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| author | Yanan Chen Rejani B Kunjamma Molly Weiner Jonah R Chan Brian Popko |
| author_facet | Yanan Chen Rejani B Kunjamma Molly Weiner Jonah R Chan Brian Popko |
| author_sort | Yanan Chen |
| collection | DOAJ |
| description | The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-γ were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of the ISR modulator Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients. |
| first_indexed | 2024-04-11T09:03:49Z |
| format | Article |
| id | doaj.art-7596443639964ebc8b31fcd2d7283054 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:03:49Z |
| publishDate | 2021-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7596443639964ebc8b31fcd2d72830542022-12-22T04:32:42ZengeLife Sciences Publications LtdeLife2050-084X2021-03-011010.7554/eLife.65469Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environmentYanan Chen0https://orcid.org/0000-0001-5510-231XRejani B Kunjamma1Molly Weiner2Jonah R Chan3https://orcid.org/0000-0002-2176-1242Brian Popko4https://orcid.org/0000-0001-9948-2553Department of Neurology, Division of Multiple Sclerosis and Neuroimmunology, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Neurology, Division of Multiple Sclerosis and Neuroimmunology, Northwestern University Feinberg School of Medicine, Chicago, United StatesDepartment of Neurology, Division of Multiple Sclerosis and Neuroimmunology, Northwestern University Feinberg School of Medicine, Chicago, United StatesWeill Institute for Neuroscience, Department of Neurology, University of California, San Francisco, San Francisco, United StatesDepartment of Neurology, Division of Multiple Sclerosis and Neuroimmunology, Northwestern University Feinberg School of Medicine, Chicago, United StatesThe inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-γ were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of the ISR modulator Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients.https://elifesciences.org/articles/65469integrated stress responseremyelinationinterferon gammaoligodendrocytecuprizonemultiple sclerosis |
| spellingShingle | Yanan Chen Rejani B Kunjamma Molly Weiner Jonah R Chan Brian Popko Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment eLife integrated stress response remyelination interferon gamma oligodendrocyte cuprizone multiple sclerosis |
| title | Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment |
| title_full | Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment |
| title_fullStr | Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment |
| title_full_unstemmed | Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment |
| title_short | Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment |
| title_sort | prolonging the integrated stress response enhances cns remyelination in an inflammatory environment |
| topic | integrated stress response remyelination interferon gamma oligodendrocyte cuprizone multiple sclerosis |
| url | https://elifesciences.org/articles/65469 |
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