Sphingosine 1-phosphate signaling at the blood-brain barrier

Briana Prager; Simona F Spampinato; Richard M Ransohoff

doi:10.1016/j.molmed.2015.03.006

Sphingosine 1-phosphate signaling at the blood-brain barrier

Trends Mol Med. 2015 Jun;21(6):354-63. doi: 10.1016/j.molmed.2015.03.006. Epub 2015 May 1.

Authors

Briana Prager¹, Simona F Spampinato², Richard M Ransohoff³

Affiliations

¹ Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
² Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
³ Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: richard.ransohoff@biogenidec.com.

PMID: 25939882
DOI: 10.1016/j.molmed.2015.03.006

Abstract

The characterization of molecular pathways that modulate blood-brain barrier (BBB) function and integrity has been fueled by a growing body of literature implicating BBB dysfunction in a wide range of neurologic diseases. Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that has been effectively targeted by the immunomodulatory S1P1 functional antagonist fingolimod in the treatment of multiple sclerosis (MS). Investigation into the pathways modulated by S1P has revealed its important role in regulating BBB integrity via signaling through receptor isoforms on astrocytes and endothelial cells (ECs). Current evidence supports a significant role for S1P signaling as a key determinant of BBB permeability and hence as a potential pathogenic player or therapeutic target in diseases characterized by BBB dysfunction.

Keywords: astrocyte; blood–brain barrier; fingolimod; multiple sclerosis; neuroinflammation; sphingosine 1-phosphate.

MeSH terms

Animals
Astrocytes / drug effects
Astrocytes / immunology
Astrocytes / metabolism
Astrocytes / pathology
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / immunology
Blood-Brain Barrier / metabolism*
Blood-Brain Barrier / pathology*
Capillary Permeability / drug effects
Endothelial Cells / drug effects
Endothelial Cells / immunology
Endothelial Cells / metabolism
Endothelial Cells / pathology
Fingolimod Hydrochloride / pharmacology
Humans
Immunologic Factors / pharmacology
Lysophospholipids / immunology
Lysophospholipids / metabolism*
Multiple Sclerosis / drug therapy
Multiple Sclerosis / immunology
Multiple Sclerosis / pathology
Receptors, Lysosphingolipid / immunology
Receptors, Lysosphingolipid / metabolism
Signal Transduction* / drug effects
Sphingosine / analogs & derivatives*
Sphingosine / immunology
Sphingosine / metabolism

Substances

Immunologic Factors
Lysophospholipids
Receptors, Lysosphingolipid
sphingosine 1-phosphate
Fingolimod Hydrochloride
Sphingosine