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

Sphingosine-l-phosphate (SIP) is a bioactive lipid that regulates ulticellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes however it is not clear whether alterations in SlP are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here using metabolomic screening we found that SlP 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 SIP 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 SIP on sickling that was independent of SIP receptor activation in isolated erythrocytes. Together our findings provide insights into erythrocyte pathophysiology revealing that a SPHK1-mediated elevation of SlP contributes to sickling and promotes disease progression and highlight potential therapeutic opportunities for SCD.