Journal
MOLECULAR NEUROBIOLOGY
Volume 56, Issue 9, Pages 5971-5986Publisher
SPRINGER
DOI: 10.1007/s12035-019-1481-x
Keywords
Astrocytes; Antigen-presenting cells (APCs); Major histocompatibility complex (MHC) class II molecules; Interferon-gamma; Fingolimod
Categories
Funding
- Slovenian Research Agency [P3-310, P3-0043]
- COST Action [BM1002]
- EU COST Action [CM1207-EuroCellNet, CM1207-GLISTEN]
- CipKeBip
- [J3 6790]
- [J3 6789]
- [J3 7605]
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Astroglia, the primary homeostatic cells of the central nervous system, play an important role in neuroinflammation. They act as facultative immunocompetent antigen-presenting cells (APCs), expressing major histocompatibility complex (MHC) class II antigens upon activation with interferon (IFN)-gamma and possibly other proinflammatory cytokines that are upregulated in disease states, including multiple sclerosis (MS). We characterized the anti-inflammatory effects of fingolimod (FTY720), an established drug for MS, and its phosphorylated metabolite (FTY720-P) in IFN-gamma-activated cultured rat astrocytes. The expression of MHC class II compartments, beta(2) adrenergic receptor (ADR-beta(2)), and nuclear factor kappa-light-chain enhancer of activated B cells subunit p65 (NF-kappa B p65) was quantified in immunofluorescence images acquired by laser scanning confocal microscopy. In addition, MHC class II-enriched endocytotic vesicles were labeled by fluorescent dextran and their mobility analyzed in astrocytes subjected to different treatments. FTY720 and FTY720-P treatment significantly reduced the number of IFN-gamma-induced MHC class II compartments and substantially increased ADR-beta(2) expression, which is otherwise small or absent in astrocytes in MS. These effects could be partially attributed to the observed decrease in NF-kappa B p65 expression, because the NF-kappa B signaling cascade is activated in inflammatory processes. We also found attenuated trafficking and secretion from dextran-labeled endo-/lysosomes that may hinder efficient delivery of MHC class II molecules to the plasma membrane. Our data suggest that FTY720 and FTY720-P at submicromolar concentrations mediate anti-inflammatory effects on astrocytes by suppressing their action as APCs, which may further downregulate the inflammatory process in the brain, constituting the therapeutic effect of fingolimod in MS.
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