Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis.
OBJECTIVE
Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P), which activates G protein-coupled receptors to regulate vascular and immune cells. The role of S1P receptors in atherosclerosis has not been examined.


RESULTS
We tested the hypothesis that S1P receptor-2 (S1PR2) regulates atherosclerosis. Apoe(-/-) S1pr2(-/-) mice showed greatly attenuated atherosclerosis compared with the Apoe(-/-) mice. Bone marrow transplant experiments indicate that S1PR2 function in the hematopoietic compartment is critical. S1PR2 is expressed in bone marrow-derived macrophages and in macrophage-like foam cells in atherosclerotic plaques. Reduced macrophage-like foam cells were found in the atherosclerotic plaques of Apoe(-/-)S1pr2(-/-) mice, suggesting that S1PR2 retains macrophages in atherosclerotic plaques. Lipoprotein profiles, plasma lipids, and oxidized low-density lipoprotein uptake by bone marrow-derived macrophages were not altered by the S1pr2 genotype. In contrast, endotoxin-induced inflammatory cytokine (interleukin [IL]-1β, IL-18) levels in the serum of S1PR2 knockout mice were significantly reduced. Furthermore, treatment of wild-type mice with S1PR2 antagonist JTE-013 suppressed IL-1β and IL-18 levels in plasma.


CONCLUSIONS
These data suggest that S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis.
Skoura
Athanasia
A
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
Michaud
Jason
J
Im
Dong-Soon
DS
Thangada
Shobha
S
Xiong
Yuquan
Y
Smith
Jonathan D
JD
Hla
Timothy
T
D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004731:Endotoxins; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood; D020382:Interleukin-18 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors
D001057:Apolipoproteins E; D004731:Endotoxins; D018836:Inflammation Mediators; D020382:Interleukin-18; D053583:Interleukin-1beta; C471998:JTE 013; D008055:Lipids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C099252:oxidized low density lipoprotein; C533955:sphingosine-1-phosphate receptor-2, mouse