Erythrocytes store and release sphingosine 1-phosphate in blood

The blood constituent sphingosine 1-phosphate (S1P) is a specific ligand for five G-protein-coupled receptors designated S1P(1-5). Expression of the S1P(1) receptor on lymphocytes is required for their exit from secondary lymphoid organs, suggesting that S1P serves as a stimulus for maintaining lymphocyte circulation in blood. Despite its potential role in immune surveillance, the regulatory system that controls blood S1P levels is not well understood. This report reveals that erythrocytes constitute a buffer system for S1P in blood. They efficiently incorporated and stored S1P, and protected it from cellular degradation. They also released S1P into plasma, but not into other serum-free media, indicating that S1P release was controlled by a plasma factor. Erythrocytes did not generate S1P since an increase in plasma S1P levels was always accompanied by a decrease in cellular S1P levels. Thrombocytes that were reported to generate and release S1P after activation did not contribute to the observed S1P release in blood. The amount of erythrocytes as well as the proportion of plasma in the medium determined the magnitude of S1P release. Adoptively transferred S1P-loaded and unloaded mouse erythrocytes displayed a normal life span and similar S1P levels 24 h after recovery, indicating that S1P incorporation and release are dynamically regulated in vivo.