Lymphocyte Sequestration Through S1P Lyase Inhibition and Disruption of S1P Gradients

TLDR

Lymphocyte egress from the thymus and peripheral lymphoid organs depends on S1P receptor‑1 and is thought to occur in response to circulatory S1P, yet the existence of an S1P gradient between lymphoid organs and blood or lymph has not been established. The study aimed to determine why treatment with the food colorant 2‑acetyl‑4‑tetrahydroxybutylimidazole (THI) induces lymphopenia. The authors investigated how THI alters lymphocyte egress by examining its effect on S1P lyase activity and the resulting S1P abundance. THI treatment increased S1P levels in lymphoid tissues by more than 100‑fold, inhibited S1P lyase, and demonstrated that lymphocyte egress is mediated by S1P gradients established by lyase activity, suggesting the lyase as a novel immunosuppressant target.

Abstract

Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 and is thought to occur in response to circulatory S1P. However, the existence of an S1P gradient between lymphoid organs and blood or lymph has not been established. To further define egress requirements, we addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. We found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after THI treatment and that this treatment inhibits the S1P-degrading enzyme S1P lyase. We conclude that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target.