Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice.
Ceramides
GTP cyclohydrolase
Nitric oxide
Omega lipids
T-cells
Tetrahydrobiopterin
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Titre abrégé: Neurotherapeutics
Pays: United States
ID NLM: 101290381
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
accepted:
15
03
2021
pubmed:
13
4
2021
medline:
4
3
2022
entrez:
12
4
2021
Statut:
ppublish
Résumé
Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice, suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 drug (sapropterin) might increase the risk of autoimmune diseases. The present study assessed the implications for multiple sclerosis (MS) as an exemplary CNS autoimmune disease. Plasma levels of biopterin were persistently low in MS patients and tended to be lower with high Expanded Disability Status Scale (EDSS). Instead, the bypass product, neopterin, was increased. The deregulation suggested that BH4 replenishment might further drive the immune response or beneficially restore the BH4 balances. To answer this question, mice were treated with sapropterin in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood. Mechanistically, sapropterin treatment was associated with increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood-brain barrier in EAE mice. Indeed, RNA data analyses revealed upregulations of genes involved in ceramide synthesis in brain endothelial cells of EAE mice (LASS6/CERS6, LASS3/CERS3, UGCG, ELOVL6, and ELOVL4). The results support the view that BH4 fortifies autoimmune CNS disease, mechanistically involving lipid deregulations that are known to contribute to the EAE pathology.
Identifiants
pubmed: 33844153
doi: 10.1007/s13311-021-01043-4
pii: 10.1007/s13311-021-01043-4
pmc: PMC8609075
doi:
Substances chimiques
Biopterins
0
Neopterin
670-65-5
sapropterin
EGX657432I
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1862-1879Subventions
Organisme : Austrian Science Fund FWF
ID : P 30800
Pays : Austria
Informations de copyright
© 2021. The Author(s).
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