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

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) repre- sents 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 ex- erts cellular effects by binding to five known GPCRs (LPA1-5). Its function in the immune sys- tem is less clear, although it was shown to induce chemotaxis of human dendritic cells (DCs) and ac- tivated 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 sat- urated LPA species are efficient chemoattractants. However, both LPA species do not alter DC matu- ration 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 ,L PA2, and LPA4 did not change. A LPA3 antagonist re- duced immature DC migration to LPA by 70%, suggesting that LPA3 mediates immature DC che- motaxis to unsaturated species of LPA. Further- more, isolated, immature DCs from mice lacking LPA3 exhibited a 50% reduction in migration to LPA. In summary, our results indicate that imma- ture mouse DCs migrate preferentially in response to unsaturated LPA and that LPA3 is important in this response. J. Leukoc. Biol. 82: 1193-1200; 2007.