Sphingosine 1-phosphate (S1P)
Physiology and the effects of S1P receptor modulation
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Abstract
Sphingosine 1-phosphate (S1P) and 5 specific high-affinity S1P receptor (S1PR) subtypes, S1P1–5, have important regulatory functions in normal physiology and disease processes, particularly involving the immune, central nervous, and cardiovascular systems. Within the immune system, downmodulation of S1P1 prevents the egress of B and T cells from lymph nodes (LN) into the lymphatic circulation. This is especially relevant in certain autoimmune diseases, including multiple sclerosis (MS), in which demyelination and brain atrophy occur due to the presence of autoreactive lymphocytes within the CNS. Accordingly, S1P1-directed pharmacologic interventions that aim to retain these autoreactive lymphocytes in the LN and thus prevent their recirculation and subsequent infiltration into the CNS have been investigated as a means of preventing disease progression in patients with MS. Fingolimod (FTY720), a structural analog of sphingosine, is phosphorylated in vivo into fingolimod phosphate by sphingosine kinase-2. Fingolimod phosphate, which binds to S1PRs, has been shown to modulate the activity of S1P1 in patients with MS and to reduce immune cell infiltration into the CNS, consistent with its previously established effects in animal models of the disease. Preclinical studies also suggest that fingolimod has beneficial effects within the CNS that are independent of its immune cell trafficking activity. This review highlights the normal physiologic processes modulated by S1P and S1PRs, and the therapeutic effects of S1PR modulation in the immune, central nervous, and cardiovascular systems.
Footnotes
Study funding: Supported by NIH grants HL67330, HL70694, and HL89934.
This Neurology® supplement is not peer-reviewed. Information contained in this Neurology® supplement represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology®.
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- ABC
- ATP-binding cassette
- LN
- lymph nodes
- MS
- multiple sclerosis
- S1P
- sphingosine 1-phosphate
- S1P1–5
- S1P receptor subtypes 1–5
- S1PR
- sphingosine 1-phosphate receptor.
- Copyright © 2011 by AAN Enterprises, Inc.
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