Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression.
Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes; however, it is not clear whether alterations in S1P are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here, using metabolomic screening, we found that S1P is highly elevated in the blood of mice and humans with SCD. In murine models of SCD, we demonstrated that elevated erythrocyte sphingosine kinase 1 (SPHK1) underlies sickling and disease progression by increasing S1P levels in the blood. Additionally, we observed elevated SPHK1 activity in erythrocytes and increased S1P in blood collected from patients with SCD and demonstrated a direct impact of elevated SPHK1-mediated production of S1P on sickling that was independent of S1P receptor activation in isolated erythrocytes. Together, our findings provide insights into erythrocyte pathophysiology, revealing that a SPHK1-mediated elevation of S1P contributes to sickling and promotes disease progression, and highlight potential therapeutic opportunities for SCD.
Yujin
Y
Zhang
Vladimir
V
Berka
Anren
A
Song
Kaiqi
K
Sun
Wei
W
Wang
Weiru
W
Zhang
Chen
C
Ning
Chonghua
C
Li
Qibo
Q
Zhang
Mikhail
M
Bogdanov
Danny C
DC
Alexander
Michael V
MV
Milburn
Mostafa H
MH
Ahmed
Han
H
Lin
Modupe
M
Idowu
Jun
J
Zhang
Gregory J
GJ
Kato
Osheiza Y
OY
Abdulmalik
Wenzheng
W
Zhang
William
W
Dowhan
Rodney E
RE
Kellems
Pumin
P
Zhang
Jianping
J
Jin
Martin
M
Safo
Ah-Lim
AL
Tsai
Harinder S
HS
Juneja
Yang
Y
Xia
D000755:Anemia, Sickle Cell / Q000097:blood* / Q000209:etiology* / Q000235:genetics; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004913:Erythrocytes, Abnormal / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000097:blood*; D055432:Metabolomics; D000432:Methanol; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D013450:Sulfones / Q000494:pharmacology; D000099157:Sphingosine Kinase
D000986:Antisickling Agents; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D000432:Methanol; D017853:Phosphotransferases (Alcohol Group Acceptor); D011759:Pyrrolidines; D013110:Sphingosine; D013450:Sulfones; D000099157:Sphingosine Kinase; C573330:PF-543; C060506:sphingosine 1-phosphate