Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Area of Science:

• Biochemistry
• Pharmacology
• Immunology

Background:

• Sphingosine 1-phosphate (S1P) gradients between blood and tissues are crucial for lymphocyte trafficking and endothelial barrier function.
• Sphingosine kinases (SphK) 1 and 2 are identified as the primary enzymes responsible for S1P biosynthesis, influencing S1P blood levels.

Purpose of the Study:

• To investigate the role of SphK isoforms in regulating blood S1P levels using novel, isoform-selective SphK inhibitors.
• To determine the mechanism by which SphK inhibition affects S1P concentrations in vivo.

Main Methods:

• Development of drug-like SphK inhibitors with varying selectivity for SphK1 and SphK2.
• Administration of inhibitors to mice and rats to assess effects on blood S1P levels.
• Pharmacokinetic studies using mass-labeled S1P in SphK2 inhibitor-treated mice and SphK2-deficient mice.

Main Results:

• SphK inhibitors decreased cellular S1P in U937 cells, but only SphK2-biased inhibitors increased blood S1P in mice and rats rapidly.
• Increased blood S1P in response to SphK2 inhibition was attributed to decreased S1P clearance, not increased synthesis.
• SphK2 demonstrates a function in S1P clearance independent of its role in S1P generation within cells.

Conclusions:

• Selective inhibition of SphK2 is a viable strategy to elevate blood S1P levels by reducing its clearance.
• This approach may allow for the manipulation of S1P levels in either direction, potentially with reduced tissue S1P concentrations.