title: Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo.
abstract: Sphingosine 1-phosphate (S1P, 1) regulates vascular barrier and lymphoid development, as well as lymphocyte egress from lymphoid organs, by activating high-affinity S1P1 receptors. We used reversible chemical probes (i) to gain mechanistic insights into S1P systems organization not accessible through genetic manipulations and (ii) to investigate their potential for therapeutic modulation. Vascular (but not airway) administration of the preferred R enantiomer of an in vivo-active chiral S1P1 receptor antagonist induced loss of capillary integrity in mouse skin and lung. In contrast, the antagonist did not affect the number of constitutive blood lymphocytes. Instead, alteration of lymphocyte trafficking and phenotype required supraphysiological elevation of S1P1 tone and was reversed by the antagonist. In vivo two-photon imaging of lymph nodes confirmed requirements for obligate agonism, and the data were consistent with the presence of a stromal barrier mechanism for gating lymphocyte egress. Thus, chemical modulation reveals differences in S1P-S1P1 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention.
authors.affiliation: Department of Immunology and The Scripps Research Institute Molecular Screening Center, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: M Germana
authors.initials: MG
authors.lastname: Sanna
authors.forename: Sheng-Kai
authors.initials: SK
authors.lastname: Wang
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Gonzalez-Cabrera
authors.forename: Anthony
authors.initials: A
authors.lastname: Don
authors.forename: David
authors.initials: D
authors.lastname: Marsolais
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Matheu
authors.forename: Sindy H
authors.initials: SH
authors.lastname: Wei
authors.forename: Ian
authors.initials: I
authors.lastname: Parker
authors.forename: Euijung
authors.initials: E
authors.lastname: Jo
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Cheng
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cahalan
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006224:Cricetinae; D004195:Disease Models, Animal; D005070:Evans Blue / Q000737:chemistry; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D063065:Organophosphonates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D010641:Phenotype; D011654:Pulmonary Edema / Q000139:chemically induced / Q000175:diagnosis; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D013237:Stereoisomerism
chemical_list: C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; D000813:Anilides; D008246:Lysophospholipids; D063065:Organophosphonates; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D005070:Evans Blue; D013110:Sphingosine