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the study authors (including Stanford geneticist Michael Snyder, PhD) identified more than 2,000 proteins that were activated in MS lesions. One of those proteins, sphingosine-1-phosphate receptor 1, was activated only in the MS brain samples, suggesting its importance in MS pathogenesis.

Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5).[1] S1PR1 was originally identified as an abundant transcript in endothelial cells[2] and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation.[3][4] In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.[5][6]

Glia. 2010 Sep;58(12):1465-76. doi: 10.1002/glia.21021.

Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions.

Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD, Van Der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE.


Source

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.


Abstract


Sphingolipids are a class of biologically active lipids that have a role in multiple biological processes including inflammation. Sphingolipids exert their functions by direct signaling or through signaling by their specific receptors. Phosphorylated FTY720 (FTY720P) is a sphingosine 1-phosphate (S1P) analogue that is currently in trial for treatment of multiple sclerosis (MS), which targets all S1P receptors but S1P(2). To date, however, it remains unknown whether FTY720P may exert direct anti-inflammatory effects within the central nervous system (CNS), because data concerning S1P receptor expression and regulation under pathological conditions in the human brain are lacking. To investigate potential regulation of S1P receptors in the human brain during MS, we performed immunohistochemical analysis of S1P receptor 1 and 3 expression in well-characterized MS lesions. A strong increase in S1P receptor 1 and 3 expression on reactive astrocytes was detected in active and chronic inactive MS lesions. In addition, we treated primary cultures of human astrocytes with the proinflammatory cytokine tumor necrosis factor-alpha to identify the regulation of S1P(1/3) on astrocytes under pathological conditions. Importantly, we demonstrate that FTY720P exerts an anti-inflammatory action on human astrocytes by limiting secretion of proinflammatory cytokines. Our data demonstrate that reactive astrocytes in MS lesions and cultured under proinflammatory conditions strongly enhance expression of S1P receptors 1 and 3. Results from this study indicate that astrocytes may act as a yet-unknown target within the CNS for the anti-inflammatory effects observed after FTY720P administration in the treatment of MS.

Under normal conditions, the brain endothelium promotes immunoquiescence of the brain by a low expression of cell adhesion molecules and undetectable detection of the production of proinflammatory cytokines and chemokines, thereby limiting attraction and subsequent transendothelial migration of leukocytes.

Moreover, in other vascular disorders, such as atherosclerosis, FTY720P exerts protective effects by dampening ongoing inflammatory processes in the vascular smooth muscle cells.

Moreover, in models of brain ischemia FTY720P was able to reduce infarct size and could, in transient focal cerebral ischemia, positively regulate neurological deficits. Observed beneficial effects were associated with a reduction in activated neutrophil and microglia/macrophage cell numbers and, in line with our results, also with reduced numbers of ICAM-1 positive blood vessels [41]

We demonstrate that endogenous endothelial S1P5 represents an essential receptor for optimal BBB function by regulating different aspects of the BBB, including the expression of cell–cell junction proteins and efflux pumps. Importantly, we demonstrate that S1P5 is essential for maintenance of the immune quiescent state of brain ECs and that this is in part mediated by NF-κB. Our data also reveal the therapeutic potential of S1P5 agonism during neuroinflammation as S1P5 specifically limits neurovascular inflammation and transendothelial leukocyte infiltration.

ThisIsMA wrote:

the study authors (including Stanford geneticist Michael Snyder, PhD) identified more than 2,000 proteins that were activated in MS lesions. One of those proteins, sphingosine-1-phosphate receptor 1, was activated only in the MS brain samples, suggesting its importance in MS pathogenesis.

Cece wrote: When they see it was active only in the MS brain samples, were the other brain samples all healthy controls? I found the actual article but it's not that clear.
http://www.nature.com/ni/journal/vaop/n ... .2730.html

ThisIsMA wrote:

Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5).[1] S1PR1 was originally identified as an abundant transcript in endothelial cells[2] and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation.[3][4] In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.[5][6]

There's a lot more to the wikipedia article if you go to the link above.

Mary Ann