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International Immunology Advance Access originally published online on May 20, 2008
International Immunology 2008 20(7):911-923; doi:10.1093/intimm/dxn050
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Sphingosine-1-phosphate receptor type-1 agonism impairs blood dendritic cell chemotaxis and skin dendritic cell migration to lymph nodes under inflammatory conditions

Gerald Gollmann1, Hannes Neuwirt2, Christoph H. Tripp3, Hansgeorg Mueller3, Guenther Konwalinka4, Christine Heufler3, Nikolaus Romani3 and Martin Tiefenthaler1

1 Division of Nephrology, Department of Internal Medicine
2 Department of Urology
3 Department of Dermatology
4 Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria

Correspondence to: H. Mueller; E-mail: hansgeorg.mueller{at}uki.at

SEW2871 is a potent sphingosine-1-phosphate receptor type-1 (S1P1)-selective agonist that induces peripheral lymphopenia through sequestration of lymphocytes into secondary lymphoid organs, similar to the non-selective sphingosine-1-phosphate (S1P) receptor agonist FTY720. FTY720 has been reported to interfere with human dendritic cell (DC) effector functions and both FTY720 and SEW2871 have been shown to modulate murine DC trafficking in vivo. Little is known about the possible effects of SEW2871 on human and murine DC functions. Here, we demonstrate that in contrast to FTY720, SEW2871 does not induce down-regulation of S1P1 in human DCs and thus does not exert a functional antagonism at S1P1. Notably, the compound was found to impair chemotaxis of immature and mature human DCs in vitro, possibly by interfering with the activation of p44/p42 and p38 mitogen-activated protein kinase signaling pathways. Comparative FACS analyses show that SEW2871 mediates CD18 down-regulation on mature human DCs. The influence on DC migration could be confirmed with in vivo assays using BALB/c mice in which SEW2871 impairs the migration of CD11c+ DC and CD207+ Langerhans cells (LC) to the draining lymph nodes (LNs) under inflammatory conditions. These results suggest that the S1P–S1P1 axis might not only control lymphocyte trafficking but also play a pivotal role in DC migration from the skin to LN.

Keywords: antigen-presenting cell, cell migration, FTY720, SEW2871, S1P

Transmitting editor: A. Falus

Received 6 November 2007, accepted 22 April 2008.


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