Sapropterin (BH4) aggravates autoimmune encephalomyelitis in mice

  • 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.
Author:Katja Schmitz, Sandra TrautmannGND, Lisa Katharina HahnefeldORCiDGND, Caroline Fischer, Yannick Schreiber, Annett Wilken-Schmitz, Robert GurkeORCiDGND, Robert BrunkhorstGND, Ernst R. Werner, Katrin WatschingerORCiD, Sabine WickerORCiDGND, Dominique Jeanette ThomasORCiDGND, Gerd GeisslingerORCiDGND, Irmgard TegederORCiD
Parent Title (English):Neurotherapeutics
Place of publication:New York, NY
Document Type:Article
Date of Publication (online):2021/04/12
Date of first Publication:2021/04/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/08/16
Tag:Ceramides; GTP cyclohydrolase; Nitric oxide; Omega lipids; T-cells; Tetrahydrobiopterin
Page Number:18
First Page:1862
Last Page:1879
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.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0