Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo.
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.
Sanna
M Germana
MG
Department of Immunology and The Scripps Research Institute Molecular Screening Center, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Wang
Sheng-Kai
SK
Gonzalez-Cabrera
Pedro J
PJ
Don
Anthony
A
Marsolais
David
D
Matheu
Melanie P
MP
Wei
Sindy H
SH
Parker
Ian
I
Jo
Euijung
E
Cheng
Wei-Chieh
WC
Cahalan
Michael D
MD
Wong
Chi-Huey
CH
Rosen
Hugh
H
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
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