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Fingolimod Suppresses the Proinflammatory Status of Interferon-γ-Activated Cultured Rat Astrocytes

  • Saša Trkov Bobnar
  • Matjaž Stenovec
  • Katarina Miš
  • Sergej Pirkmajer
  • Robert ZorecEmail author
Article
  • 55 Downloads

Abstract

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)-γ 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-γ-activated cultured rat astrocytes. The expression of MHC class II compartments, β2 adrenergic receptor (ADR-β2), and nuclear factor kappa-light-chain enhancer of activated B cells subunit p65 (NF-κB 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-γ-induced MHC class II compartments and substantially increased ADR-β2 expression, which is otherwise small or absent in astrocytes in MS. These effects could be partially attributed to the observed decrease in NF-κB p65 expression, because the NF-κB 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.

Keywords

Astrocytes Antigen-presenting cells (APCs) Major histocompatibility complex (MHC) class II molecules Interferon-γ Fingolimod 

Notes

Funding

The authors acknowledge the financial support from the Slovenian Research Agency (research core funding P3-310 and P3-0043) and projects J3 6790, J3 6789, and J3 7605, CipKeBip, COST Action BM1002, EU COST Action CM1207—GLISTEN, and EU COST Action CM1207—EuroCellNet.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. Care of the experimental animals was in accordance with European and Slovenian legislation (Official Gazette of the RS 38/13; UVHVVR, no. U34401-47/2014/7). This article does not contain any studies with human participants performed by any of the authors.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
  2. 2.Celica BiomedicalLjubljanaSlovenia
  3. 3.Laboratory for Molecular Neurobiology, Institute of Pathophysiology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia

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