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Research ArticleArticle

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

David Marsolais, Bumsuk Hahm, Kurt H. Edelmann, Kevin B. Walsh, Miguel Guerrero, Yasuko Hatta, Yoshihiro Kawaoka, Edward Roberts, Michael B. A. Oldstone and Hugh Rosen
Molecular Pharmacology September 2008, 74 (3) 896-903; DOI: https://doi.org/10.1124/mol.108.048769
David Marsolais
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Bumsuk Hahm
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Kurt H. Edelmann
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Kevin B. Walsh
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Miguel Guerrero
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Yasuko Hatta
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Yoshihiro Kawaoka
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Edward Roberts
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Michael B. A. Oldstone
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Hugh Rosen
Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)
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Abstract

The mechanism by which locally delivered sphingosine analogs regulate host response to localized viral infection has never been addressed. In this report, we show that intratracheal delivery of the chiral sphingosine analog (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (AAL-R) or its phosphate ester inhibits the T-cell response to influenza virus infection. In contrast, neither intraperitoneal delivery of AAL-R nor intratracheal instillation of the non-phosphorylatable stereoisomer AAL-S suppressed virus-specific T-cell response, indicating that in vivo phosphorylation of AAL-R and sphingosine 1-phosphate (S1P) receptor modulation in lungs is essential for immunomodulation. Intratracheal delivery of water-soluble S1P1 receptor agonist at doses sufficient to induce systemic lymphopenia did not inhibit virus-specific T-cell response, indicating that S1P1 is not involved in the immunosuppressive activities of AAL-R and that immunosuppression acts independently of naive lymphocyte recirculation. Accumulation of dendritic cells (DCs) in draining lymph nodes was inhibited by intratracheal but not intraperitoneal delivery of AAL-R. Direct modulation of DCs is demonstrated by the impaired ability of virus-infected bone marrow-derived DCs treated in vitro with AAL-R to trigger in vivo T-cell response after adoptive transfer to the airways. Thus, our results suggest that locally delivered sphingosine analogs induce immunosuppression by modulating S1P receptors other than S1P1 or S1P2 on dendritic cells in the lungs after influenza virus infection.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (3)
Molecular Pharmacology
Vol. 74, Issue 3
1 Sep 2008
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Research ArticleArticle

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

David Marsolais, Bumsuk Hahm, Kurt H. Edelmann, Kevin B. Walsh, Miguel Guerrero, Yasuko Hatta, Yoshihiro Kawaoka, Edward Roberts, Michael B. A. Oldstone and Hugh Rosen
Molecular Pharmacology September 1, 2008, 74 (3) 896-903; DOI: https://doi.org/10.1124/mol.108.048769

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Research ArticleArticle

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

David Marsolais, Bumsuk Hahm, Kurt H. Edelmann, Kevin B. Walsh, Miguel Guerrero, Yasuko Hatta, Yoshihiro Kawaoka, Edward Roberts, Michael B. A. Oldstone and Hugh Rosen
Molecular Pharmacology September 1, 2008, 74 (3) 896-903; DOI: https://doi.org/10.1124/mol.108.048769
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