Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate.
Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin, with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives.
Pappu
Rajita
R
Cardiovascular Research Institute, University of California, San Francisco, 600 16th Street S472D, San Francisco, CA 94143-2240, USA.
Schwab
Susan R
SR
Cornelissen
Ivo
I
Pereira
João P
JP
Regard
Jean B
JB
Xu
Ying
Y
Camerer
Eric
E
Zheng
Yao-Wu
YW
Huang
Yong
Y
Cyster
Jason G
JG
Coughlin
Shaun R
SR
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D002853:Chromatography, Liquid; D004730:Endothelium, Vascular; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000502:physiology*; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000097:blood / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000502:physiology; D053719:Tandem Mass Spectrometry; D000099157:Sphingosine Kinase
D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate