Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression

Yujin Zhang, Vladimir Berka, Anren Song, Kaiqi Sun, Wei Wang, Weiru Zhang, Chen Ning, Chonghua Li, Qibo Zhang, Mikhail Bogdanov, Danny C. Alexander, Michael V. Milburn, Mostafa H. Ahmed, Han Lin, Modupe Idowu, Jun Zhang, Gregory J. Kato, Osheiza Y. Abdulmalik, Wenzheng Zhang, William DowhanRodney E. Kellems, Pumin Zhang, Jianping Jin, Martin Safo, Ah Lim Tsai, Harinder S. Juneja, Yang Xia

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2750-2761
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
StatePublished - Jun 2 2014

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression'. Together they form a unique fingerprint.

Cite this