Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis.
Previous studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4460035?pdf=render |
| _version_ | 1818689416553562112 |
|---|---|
| author | Izabella Solti Krisztian Kvell Gergely Talaber Sara Veto Peter Acs Ferenc Gallyas Zsolt Illes Katalin Fekete Petra Zalan Arpad Szanto Zita Bognar |
| author_facet | Izabella Solti Krisztian Kvell Gergely Talaber Sara Veto Peter Acs Ferenc Gallyas Zsolt Illes Katalin Fekete Petra Zalan Arpad Szanto Zita Bognar |
| author_sort | Izabella Solti |
| collection | DOAJ |
| description | Previous studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first time, how cuprizone feeding affects the thymus, the organ of T-cell maturation and selection. We found that even one week of cuprizone treatment induced significant thymic atrophy, affecting the cortex over the medulla. Fluorescent microscopy and flow-cytometric analyses of thymi from cuprizone- and vehicle-treated mice indicated that eradication of the cluster of the differentiation-4 (CD4)-CD8 double-positive T-cell subset was behind the substantial cell loss. This result was confirmed with CD3-CD4-CD8 triple-staining experiments. Ultrastructurally, we observed degraded as well as enlarged mitochondria, myelin-bodies, large lipid droplets, and large lysosomes in the thymi of cuprizone-treated mice. Some of these features were similar to those in physiological and steroid-induced accelerated aging. According to our results, apoptosis was mainly of mitochondrial origin mediated by both caspase-3- and apoptosis inducing factor-mediated mechanisms. Additionally, mitogen activated protein kinase activation and increased pro-apoptotic B cell lymphoma-2 family protein expression were the major underlying processes. Our results do not indicate a functional relationship between cuprizone-induced thymus involution and the absence of inflammatory responses or the selective demyelination observed in the cuprizone model. On the other hand, due to the reversible nature of cuprizone's deleterious effects, the cuprizone model could be valuable in studying thymus regeneration as well as remyelination processes. |
| first_indexed | 2024-12-17T12:09:46Z |
| format | Article |
| id | doaj.art-cdf0c09afbda4a2f891df94e32f4ac79 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T12:09:46Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-cdf0c09afbda4a2f891df94e32f4ac792022-12-21T21:49:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01106e012921710.1371/journal.pone.0129217Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis.Izabella SoltiKrisztian KvellGergely TalaberSara VetoPeter AcsFerenc GallyasZsolt IllesKatalin FeketePetra ZalanArpad SzantoZita BognarPrevious studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first time, how cuprizone feeding affects the thymus, the organ of T-cell maturation and selection. We found that even one week of cuprizone treatment induced significant thymic atrophy, affecting the cortex over the medulla. Fluorescent microscopy and flow-cytometric analyses of thymi from cuprizone- and vehicle-treated mice indicated that eradication of the cluster of the differentiation-4 (CD4)-CD8 double-positive T-cell subset was behind the substantial cell loss. This result was confirmed with CD3-CD4-CD8 triple-staining experiments. Ultrastructurally, we observed degraded as well as enlarged mitochondria, myelin-bodies, large lipid droplets, and large lysosomes in the thymi of cuprizone-treated mice. Some of these features were similar to those in physiological and steroid-induced accelerated aging. According to our results, apoptosis was mainly of mitochondrial origin mediated by both caspase-3- and apoptosis inducing factor-mediated mechanisms. Additionally, mitogen activated protein kinase activation and increased pro-apoptotic B cell lymphoma-2 family protein expression were the major underlying processes. Our results do not indicate a functional relationship between cuprizone-induced thymus involution and the absence of inflammatory responses or the selective demyelination observed in the cuprizone model. On the other hand, due to the reversible nature of cuprizone's deleterious effects, the cuprizone model could be valuable in studying thymus regeneration as well as remyelination processes.http://europepmc.org/articles/PMC4460035?pdf=render |
| spellingShingle | Izabella Solti Krisztian Kvell Gergely Talaber Sara Veto Peter Acs Ferenc Gallyas Zsolt Illes Katalin Fekete Petra Zalan Arpad Szanto Zita Bognar Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis. PLoS ONE |
| title | Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis. |
| title_full | Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis. |
| title_fullStr | Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis. |
| title_full_unstemmed | Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis. |
| title_short | Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis. |
| title_sort | thymic atrophy and apoptosis of cd4 cd8 thymocytes in the cuprizone model of multiple sclerosis |
| url | http://europepmc.org/articles/PMC4460035?pdf=render |
| work_keys_str_mv | AT izabellasolti thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT krisztiankvell thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT gergelytalaber thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT saraveto thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT peteracs thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT ferencgallyas thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT zsoltilles thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT katalinfekete thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT petrazalan thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT arpadszanto thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis AT zitabognar thymicatrophyandapoptosisofcd4cd8thymocytesinthecuprizonemodelofmultiplesclerosis |