title: The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis regulates early airway T-cell infiltration in murine mast cell-dependent acute allergic responses.
abstract: BACKGROUND
  Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid produced by mast cells (MCs) on cross-linking of their high-affinity receptors for IgE by antigen that can amplify MC responses by binding to its S1P receptors. An acute MC-dependent allergic reaction can lead to systemic shock, but the early events of its development in lung tissues have not been investigated, and S1P functions in the onset of allergic processes remain to be examined.
  
  
  OBJECTIVE
  We used a highly specific neutralizing anti-S1P antibody (mAb) and the sphingosine-1-phosphate receptor 2 (S1PR2) antagonist JTE-013 to study the signaling contributions of S1P and S1PR2 to MC- and IgE-dependent airway allergic responses in mice within minutes after antigen challenge.
  
  
  METHODS
  Allergic reaction was triggered by a single intraperitoneal dose of antigen in sensitized mice pretreated intraperitoneally with anti-S1P, isotype control mAb, JTE-013, or vehicle before antigen challenge.
  
  
  RESULTS
  Kinetics experiments revealed early pulmonary infiltration of mostly T cells around blood vessels of sensitized mice 20 minutes after antigen exposure. Pretreatment with anti-S1P mAb inhibited in vitro MC activation, as well as in vivo development of airway infiltration and MC activation, reducing serum levels of histamine, cytokines, and the chemokines monocyte chemoattractant protein 1/CCL2, macrophage inflammatory protein 1α/CCL3, and RANTES/CCL5. S1PR2 antagonism or deficiency or MC deficiency recapitulated these results. Both in vitro and in vivo experiments demonstrated MC S1PR2 dependency for chemokine release and the necessity for signal transducer and activator of transcription 3 activation.
  
  
  CONCLUSIONS
  Activation of S1PR2 by S1P and downstream signal transducer and activator of transcription 3 signaling in MCs regulate early T-cell recruitment to antigen-challenged lungs through chemokine production.
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va. Electronic address: Carole.Oskeritzian@uscmed.sc.edu.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Oskeritzian
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC.
authors.forename: Piper
authors.initials: P
authors.lastname: Wedman
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC.
authors.forename: Alena
authors.initials: A
authors.lastname: Chumanevich
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Va.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kolawole
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Price
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Va.
authors.forename: Yves T
authors.initials: YT
authors.lastname: Falanga
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Kuzhuvelil B
authors.initials: KB
authors.lastname: Harikumar
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, Va.
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: Lpath, San Diego, Calif.
authors.forename: Roger
authors.initials: R
authors.lastname: Sabbadini
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000941:Antigens; D018925:Chemokines; D016207:Cytokines; C471998:JTE 013; D008246:Lysophospholipids; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D050796:STAT3 Transcription Factor; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: Airway inflammation; T cells; allergy; mast cells; recruitment; signal transducer and activator of transcription 3; sphingosine-1-phosphate; sphingosine-1-phosphate receptor 2