title: Sphingosine 1-phosphate-induced motility and endocytosis of dendritic cells is regulated by SWAP-70 through RhoA.
abstract: The phospholipid mediator sphingosine 1-phosphate (S1P) enhances motility and endocytosis of mature dendritic cells (DCs). We show that in vitro migration of Swap-70(-/-) bone marrow-derived DCs (BMDCs) in response to S1P and S1P-induced upregulation of endocytosis are significantly reduced. S1P-stimulated movement of Swap-70(-/-) BMDCs, specifically retraction of their trailing edge, in a collagen three-dimensional environment is impaired. These in vitro observations correlate with delayed entry into lymphatic vessels and migration to lymph nodes of skin DCs in Swap-70(-/-) mice. Expression of S1P receptors (S1P(1-3)) by wild-type and Swap-70(-/-) BMDCs is similar, but Swap-70(-/-) BMDCs fail to activate RhoA and to localize Rac1 and RhoA into areas of actin polymerization after S1P stimulus. The Rho-activating G protein Gα(i) interacts with SWAP-70, which also supports the localization of Gα(13) to membrane rafts in BMDCs. LPS-matured Swap-70(-/-) BMDCs contain significantly more active RhoA than wild-type DCs. Preinhibition of Rho activation restored migration to S1P, S1P-induced upregulation of endocytosis in mature Swap-70(-/-) BMDCs, and localization of Gα(13) to membrane rafts. These data demonstrate SWAP-70 as a novel regulator of S1P signaling necessary for DC motility and endocytosis.
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Institute of Physiological Chemistry, Dresden University of Technology, D-01307 Dresden, Germany. carlos.ocana-morgner@mailbox.tu-dresden.de
authors.forename: Carlos
authors.initials: C
authors.lastname: Ocaña-Morgner
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Michaël
authors.initials: M
authors.lastname: Chopin
authors.forename: Sarah
authors.initials: S
authors.lastname: Braungart
authors.forename: Christine
authors.initials: C
authors.lastname: Wahren
authors.forename: Matthias
authors.initials: M
authors.lastname: Gunzer
authors.forename: Rolf
authors.initials: R
authors.lastname: Jessberger
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D005434:Flow Cytometry; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D047468:Immunoprecipitation; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D008246:Lysophospholipids; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; C113365:Swap70 protein, mouse; C060506:sphingosine 1-phosphate; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D013110:Sphingosine