title: Dendritic cell sphingosine 1-phosphate receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion injury.
abstract: Dendritic cells (DCs) are central to innate and adaptive immunity of early kidney ischemia-reperfusion injury (IRI), and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5), and protection from kidney IRI occurs in S1P3-deficient mice. Through a series of experiments we determined that this protective effect was owing in part to differences between S1P3-sufficient and -deficient DCs. Mice lacking S1P3 on bone marrow cells were protected from IRI, and S1P3-deficient DCs displayed an immature phenotype. Wild-type (WT) but not S1P3-deficient DCs injected into mice depleted of DCs prior to kidney IR reconstituted injury. Adoptive transfer (i.e., i.v. injection) of glycolipid (Ag)-loaded WT but not S1P3-deficient DCs into WT mice exacerbated IRI, suggesting that WT but not S1P3-deficient DCs activated NKT cells. Whereas WT DC transfers activated the Th1/IFN-γ pathway, S1P3-deficient DCs activated the Th2/IL-4 pathway, and an IL-4-blocking Ab reversed protection from IRI, supporting the concept that IL-4 mediates the protective effect of S1P3-deficient DCs. Administration of S1P3-deficient DCs 7 d prior to or 3 h after IRI protected mice from IRI and suggests their potential use in cell-based therapy. We conclude that absence of DC S1P3 prevents DC maturation and promotes a Th2/IL-4 response. These findings highlight the importance of DC S1P3 in modulating NKT cell function and IRI and support development of selective S1P3 antagonists for tolerizing DCs for cell-based therapy or for systemic administration for the prevention and treatment of IRI and autoimmune diseases.
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA. ab9nh@virginia.edu
authors.forename: Amandeep
authors.initials: A
authors.lastname: Bajwa
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Krishna
authors.initials: K
authors.lastname: Dondeti
authors.forename: Steven
authors.initials: S
authors.lastname: Song
authors.forename: Diane L
authors.initials: DL
authors.lastname: Rosin
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Peter I
authors.initials: PI
authors.lastname: Lobo
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007511:Ischemia / Q000276:immunology / Q000473:pathology*; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000276:immunology; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology; D000081025:Sphingosine-1-Phosphate Receptors; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors