Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis
Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood br...
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MDPI AG
2019-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/11/1314 |
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| author | Monokesh K. Sen Mohammed S. M. Almuslehi Erika Gyengesi Simon J. Myers Peter J. Shortland David A. Mahns Jens R. Coorssen |
| author_facet | Monokesh K. Sen Mohammed S. M. Almuslehi Erika Gyengesi Simon J. Myers Peter J. Shortland David A. Mahns Jens R. Coorssen |
| author_sort | Monokesh K. Sen |
| collection | DOAJ |
| description | Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis <i>plus</i> marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and <i>no</i> splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement. |
| first_indexed | 2024-03-12T08:02:26Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T08:02:26Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ed9d0b60ba134912b828fce35e51db1a2023-09-02T19:49:02ZengMDPI AGCells2073-44092019-10-01811131410.3390/cells8111314cells8111314Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple SclerosisMonokesh K. Sen0Mohammed S. M. Almuslehi1Erika Gyengesi2Simon J. Myers3Peter J. Shortland4David A. Mahns5Jens R. Coorssen6School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, AustraliaSchool of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, AustraliaSchool of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, AustraliaSchool of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, AustraliaSchool of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, AustraliaSchool of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, AustraliaDepartment of Health Sciences, Faculty of Applied Health Sciences, and Department of Biological Sciences, Faculty of Mathematics and Science, Brock University, St. Catharines, Ontario, ON L2S 3A1, CanadaCuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis <i>plus</i> marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and <i>no</i> splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.https://www.mdpi.com/2073-4409/8/11/1314inside-outoutside-inoligodendrocytosisdemyelinationgliosishistologytop-down proteomicsbioinformaticsmitochondria |
| spellingShingle | Monokesh K. Sen Mohammed S. M. Almuslehi Erika Gyengesi Simon J. Myers Peter J. Shortland David A. Mahns Jens R. Coorssen Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis Cells inside-out outside-in oligodendrocytosis demyelination gliosis histology top-down proteomics bioinformatics mitochondria |
| title | Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis |
| title_full | Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis |
| title_fullStr | Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis |
| title_full_unstemmed | Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis |
| title_short | Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis |
| title_sort | suppression of the peripheral immune system limits the central immune response following cuprizone feeding relevance to modelling multiple sclerosis |
| topic | inside-out outside-in oligodendrocytosis demyelination gliosis histology top-down proteomics bioinformatics mitochondria |
| url | https://www.mdpi.com/2073-4409/8/11/1314 |
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