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Published online before print August 20, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0407221

Received for publication April 12, 2007.
Revised July 3, 2007.
Accepted for publication July 6, 2007.

Article

LPA₃ receptor mediates chemotaxis of immature murine dendritic cells to unsaturated lysophosphatidic acid (LPA)

Liana C. Chan ^*, Wendy Peters ^*, Yan Xu , Jerold Chun , Robert V. Farese Jr.^*, and Sylvaine Cases ^*@

*Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California, USA; and Cardiovascular Research Institute, Departments of Medicine and Biochemistry & Biophysics, and Diabetes Center, University of California, San Francisco, California, USA

^@ To whom correspondence should be addressed. E-mail: scases{at}gladstone.ucsf.edu.

	Abstract

Increasing evidence supports roles for lipids in the biology of immune cells. In particular, bioactive lipids such as sphingosine-1-phosphate (S1P) bind to cognate G protein-coupled receptors (GPCRs) and modulate leukocyte trafficking and homeostasis. Lysophosphatidic acid (LPA) represents a family of bioactive lipids, which differ in the length and degree of saturation of the fatty acyl chain. LPA is structurally related to S1P and exerts cellular effects by binding to five known GPCRs (LPA_1–5). Its function in the immune system is less clear, although it was shown to induce chemotaxis of human dendritic cells (DCs) and activated T cells. In this study, we show that LPA can induce chemotaxis of immature but not mature mouse DCs and that only unsaturated and not saturated LPA species are efficient chemoattractants. However, both LPA species do not alter DC maturation or chemotaxis to other chemokines. The loss of DC migration capability correlated with the down-regulation of expression of the receptors LPA₃ and LPA₅, and expression of LPA₁, LPA₂, and LPA₄ did not change. A LPA₃ antagonist reduced immature DC migration to LPA by 70%, suggesting that LPA₃ mediates immature DC chemotaxis to unsaturated species of LPA. Furthermore, isolated, immature DCs from mice lacking LPA₃ exhibited a 50% reduction in migration to LPA. In summary, our results indicate that immature mouse DCs migrate preferentially in response to unsaturated LPA and that LPA₃ is important in this response.

Key Words: sphingosine-1-phosphate • GPCR

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