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Rapid CommunicationAccelerated Communication

Sphingosine 1-Phosphate Receptor 1 (S1P1) Upregulation and Amelioration of Experimental Autoimmune Encephalomyelitis by an S1P1 Antagonist

Stuart M. Cahalan, Pedro J. Gonzalez-Cabrera, Nhan Nguyen, Miguel Guerrero, Elizabeth A. George Cisar, Nora B. Leaf, Steven J. Brown, Edward Roberts and Hugh Rosen
Molecular Pharmacology February 2013, 83 (2) 316-321; DOI: https://doi.org/10.1124/mol.112.082958
Stuart M. Cahalan
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Pedro J. Gonzalez-Cabrera
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Nhan Nguyen
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Miguel Guerrero
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Elizabeth A. George Cisar
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Nora B. Leaf
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Steven J. Brown
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Edward Roberts
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Hugh Rosen
Departments of Chemical Physiology (S.M.C., P.J.G.-C., N.N., E.A.G.C., N.B.L., S.J.B., H.R.) and Chemistry (M.G., E.R.), The Scripps Research Institute, La Jolla, California
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Abstract

Sphingosine 1-phosphate receptor 1 (S1P1) is a G protein–coupled receptor that is critical for proper lymphocyte development and recirculation. Agonists to S1P1 are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P1 expressed on lymphocytes and S1P1 expressed within the central nervous system. Agonists to S1P1 and deficiency in S1P1 both cause lymphocyte sequestration in the lymph nodes. In the present study, we show that S1P1 antagonism induces lymphocyte sequestration in the lymph nodes similar to that observed with S1P1 agonists while upregulating S1P1 on lymphocytes and endothelial cells. Additionally, we show that S1P1 antagonism reverses experimental autoimmune encephalomyelitis in mice without acting on S1P1 expressed within the central nervous system, demonstrating that lymphocyte sequestration via S1P1 antagonism is sufficient to alleviate autoimmune pathology.

Footnotes

  • This work was funded by National Institutes of Health [Grants AI05509, AI074564, and MH084812].

  • dx.doi.org/10.1124/mol.112.082958.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received October 12, 2012.
  • Accepted November 30, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (2)
Molecular Pharmacology
Vol. 83, Issue 2
1 Feb 2013
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Rapid CommunicationAccelerated Communication

S1P1 Antagonist Reverses EAE Independent of CNS S1P1

Stuart M. Cahalan, Pedro J. Gonzalez-Cabrera, Nhan Nguyen, Miguel Guerrero, Elizabeth A. George Cisar, Nora B. Leaf, Steven J. Brown, Edward Roberts and Hugh Rosen
Molecular Pharmacology February 1, 2013, 83 (2) 316-321; DOI: https://doi.org/10.1124/mol.112.082958

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Rapid CommunicationAccelerated Communication

S1P1 Antagonist Reverses EAE Independent of CNS S1P1

Stuart M. Cahalan, Pedro J. Gonzalez-Cabrera, Nhan Nguyen, Miguel Guerrero, Elizabeth A. George Cisar, Nora B. Leaf, Steven J. Brown, Edward Roberts and Hugh Rosen
Molecular Pharmacology February 1, 2013, 83 (2) 316-321; DOI: https://doi.org/10.1124/mol.112.082958
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