Sphingosine-1-phosphate mediates migration of mature dendritic cells

Sphingosine-1-phosphate (S1P) represents a potent modulator of diverse cellular activities, including lymphocyte trafficking and maintenance of lymphocyte homeostasis. The five known receptors for SIP (S1P(1-5)) belong to the family of G protein-coupled receptors. Upon binding SIP, they act downstream via heterotrimeric G proteins on members of the small GTPase family (Cdc42/Rac/Rho), evoking a SIP receptor-dependent activation pattern of Cdc42, Rac, and Rho, respectively. This, in turn, triggers cytoskeletal rearrangements determining cellular morphology and movement. In this study we investigated the effects of SIP on murine dendritic cells (DC). Mature DC, but not immature in vitro differentiated DC, were found to migrate to SIP, a phenomenon that correlated to the up-regulation of SIP, and S1P, in maturing DC. The same pattern of SIP receptor regulation could be observed in vivo on skin DC after their activation and migration into the lymph node. The migration-inducing effect of SIP could be severely hampered by application of the SIP analogon FTY720 in vitro and in vivo. A similar, yet more pronounced, block was observed upon preventing Cdc42/Rac and/or Rho activation by specific inhibitors. These results suggest that S1P-mediated signaling plays a pivotal role in the life cycle of DC.