Abstract 3610: Haematopoietic Absence of Sphingosine 1-Phosphate Lyase Decreases Atherosclerotic Lesion Development in LDL-Receptor Deficient Mice
Sphingosine 1-phosphate (S1P), a bioactive lipid and key regulator of leukocyte migration, has been implicated in atherosclerosis in both LDLr−/− and ApoE−/− mice by virtue of its anti-inflammatory properties. S1P levels are tightly controlled by S1P lyase, an enzyme catalyzing S1P breakdown. Based on these findings, we investigated the role of S1P lyase, encoded by Sgpl1, in the maintenance of S1P gradients in haematopoietic cells, leukocyte homeostasis and atherosclerosis in mice. Irradiated female LDLr−/− recipients received 5*106 bone marrow cells from Sgpl1−/− or +/+ littermates. After recovery, mice were fed a high fat diet for 4 weeks. These studies revealed that the hyperlipidemic response to a high fat diet was severely hampered in mice receiving Sgpl1−/− bone marrow cells, as evidenced by blunted increases in plasma triglyceride, total cholesterol and phospholipid (P<0.05), as well as a less atherogenic lipoprotein profile. These effects were likely attributable to perturbed fat absorption rather than VLDL secretion. Moreover, while total S1P levels in serum were only modestly elevated (1.25-fold, p<0.01), S1P levels were increased 2.2-fold in the thymus and more than 40-fold in the spleen, lymph nodes and liver (P<0.01). As the establishment of S1P gradients is crucial for lymphocyte egress from lymphoid organs, the lymphocyte distribution and trafficking has been examined in Sgpl1−/− chimeras. FACS analysis revealed a 55% reduction in CD4+ and CD8+ T-cells in blood, lymph nodes and spleen (P<0.001), with a relative enrichment of T-cell migration (CCR7, CXCR4, S1P1) and activation (CD45RA, CD69) markers (P<0.01). In addition, lymphocytes showed a reduced migratory response towards CCL19, reduced homing in adoptive transfer studies and a decreased mitogenic response to ConA (P<0.05). Finally, atherosclerotic lesion formation in Sgpl1−/− chimeras was reduced by 35% (1.05*105 μm2 vs. 1.62*105 μm2, P=0.02). In addition, no changes were seen on plaque macrophage content, while a trend was seen towards a reduced T cell content. Collectively, these findings suggest that modulation of S1P signalling by absence of haematopoietic S1P lyase inhibits atherosclerosis by both improving the lipid balance and modulating the leukocyte homeostasis.