Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?

PLoS One. 2015 Jul 21;10(7):e0133392. doi: 10.1371/journal.pone.0133392. eCollection 2015.


The ability of the Blood Brain Barrier (BBB) to maintain proper barrier functions, keeping an optimal environment for central nervous system (CNS) activity and regulating leukocytes' access, can be affected in CNS diseases. Endothelial cells and astrocytes are the principal BBB cellular constituents and their interaction is essential to maintain its function. Both endothelial cells and astrocytes express the receptors for the bioactive sphingolipid S1P. Fingolimod, an immune modulatory drug whose structure is similar to S1P, has been approved for treatment in multiple sclerosis (MS): fingolimod reduces the rate of MS relapses by preventing leukocyte egress from the lymph nodes. Here, we examined the ability of S1P and fingolimod to act on the BBB, using an in vitro co-culture model that allowed us to investigate the effects of S1P on endothelial cells, astrocytes, and interactions between the two. Acting selectively on endothelial cells, S1P receptor signaling reduced cell death induced by inflammatory cytokines. When acting on astrocytes, fingolimod treatment induced the release of a factor, granulocyte macrophage colony-stimulating factor (GM-CSF) that reduced the effects of cytokines on endothelium. In an in vitro BBB model incorporating shear stress, S1P receptor modulation reduced leukocyte migration across the endothelial barrier, indicating a novel mechanism that might contribute to fingolimod efficacy in MS treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Astrocytes / cytology*
  • Astrocytes / metabolism
  • Blood-Brain Barrier / metabolism*
  • Cell Movement
  • Cell Survival
  • Cytokines / metabolism
  • Endothelial Cells / cytology*
  • Fingolimod Hydrochloride / chemistry
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Healthy Volunteers
  • Humans
  • Inflammation
  • Leukocytes / cytology
  • Lysophospholipids / metabolism*
  • Microcirculation
  • Middle Aged
  • Multiple Sclerosis / immunology*
  • Receptors, Lysosphingolipid / metabolism*
  • Signal Transduction
  • Sphingolipids / chemistry
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Stress, Mechanical
  • Young Adult


  • Cytokines
  • Lysophospholipids
  • Receptors, Lysosphingolipid
  • Sphingolipids
  • sphingosine 1-phosphate
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Fingolimod Hydrochloride
  • Sphingosine

Grants and funding

The study was supported by Novartis funding #CFTY7220DUSNC10T. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.