Article ; Online: Inhibition of SUMOylation promotes remyelination and reduces IL-17 mediated autoimmune inflammation: Novel approach toward treatment of inflammatory CNS demyelinating disease.
2023 Volume 384, Page(s) 578219
Abstract: Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state of SUMOylation of their respective transcription factors. In the immune system, ... ...
| Abstract | Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state of SUMOylation of their respective transcription factors. In the immune system, deSUMOylation activates innate immune responses and promotes anti-viral immunity. However, the role played by SUMO in an adaptive immune response and in the development of T cell mediated autoimmune disease has not been previously described. TAK981 is a synthetic small molecule which by forming adducts with SUMO proteins prevents SUMOylation. We examined the expression of myelin genes and their transcription factors following culture with TAK981 in Oligodendrocyte Precursor Cells (OPC). We found that myelin basic protein (MBP), a key myelin protein, is upregulated in OPC in the presence of TAK981. We also found increased expression of transcription factors Sox10 and Myrf, which engage in the expression of MBP. In the Cuprizone model of demyelination/remyelination, animals which were treated with TAK981 showed increased remyelination in areas of demyelination and an increase in the number of maturing oligodendrocytes compared to vehicle treated controls. In in vitro cultures of lymphocytes, TAK981 reduced the expression of TH17 in T cells in mice immunized with MOGp35-55. Following in vivo treatment with TAK981, there was a significant reduction in the clinical and pathological severity in mice immunized to develop experimental allergic encephalitis (EAE). The dual effects of deSUMOylation on remyelination and in regulating an autoimmune adaptive response offers a novel approach to the management of human inflammatory demyelinating diseases such as multiple sclerosis. |
|---|---|
| MeSH term(s) | Mice ; Humans ; Animals ; Demyelinating Diseases/chemically induced ; Demyelinating Diseases/drug therapy ; Demyelinating Diseases/metabolism ; Remyelination/physiology ; Sumoylation ; Interleukin-17 ; Cell Differentiation ; Myelin Sheath/pathology ; Oligodendroglia/metabolism ; Cuprizone/toxicity ; Inflammation/drug therapy ; Inflammation/metabolism ; Central Nervous System Diseases/metabolism ; Transcription Factors/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal |
| Chemical Substances | Interleukin-17 ; Cuprizone (5N16U7E0AO) ; Transcription Factors |
| Language | English |
| Publishing date | 2023-10-04 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 8335-5 |
| ISSN | 1872-8421 ; 0165-5728 |
| ISSN (online) | 1872-8421 |
| ISSN | 0165-5728 |
| DOI | 10.1016/j.jneuroim.2023.578219 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 1646: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.