TY  - JOUR
A1  - Schmitz, Katja
A1  - Trautmann, Sandra
A1  - Hahnefeld, Lisa Katharina
A1  - Fischer, Caroline
A1  - Schreiber, Yannick
A1  - Wilken-Schmitz, Annett
A1  - Gurke, Robert
A1  - Brunkhorst, Robert
A1  - Werner, Ernst R.
A1  - Watschinger, Katrin
A1  - Wicker, Sabine
A1  - Thomas, Dominique Jeanette
A1  - Geisslinger, Gerd
A1  - Tegeder, Irmgard
T1  - Sapropterin (BH4) aggravates autoimmune encephalomyelitis in mice
T2  - Neurotherapeutics
N2  - 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.
KW  - Tetrahydrobiopterin
KW  - T-cells
KW  - GTP cyclohydrolase
KW  - Nitric oxide
KW  - Ceramides
KW  - Omega lipids
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63639
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-636394
SN  - 1878-7479
N1  - Open Access funding enabled and organized by Projekt DEAL. The study was supported by the Deutsche Forschungsgemeinschaft (SFB815, A12 to IT and CRC1039 A03 to IT and CRC1039 Z01 to GG) and the Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD to GG) and the Austrian Science Fund (P-30800 to KW). The funding institution had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.
VL  - 18.2021
IS  - 3
SP  - 1862
EP  - 1879
PB  - Springer
CY  - New York, NY
ER  -