Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in several physiological processes including cell migration and differentiation. S1P signaling is mediated through five G protein-coupled receptors (S1P1-S1P5). S1P1 is crucial to the exit of T-lymphocytes from the thymus and peripheral lymphoid organs through a gradient of S1P. We have previously observed that T-ALL and T-LBL blasts express S1P1. Herein we analyzed the role of S1P receptors in the migratory pattern of human T-cell neoplastic blasts. S1P-triggered cell migration was directly related to S1P1 expression. T-ALL blasts expressing low levels of S1P1 mRNA (HPB-ALL) did not migrate toward S1P, whereas those expressing higher levels of S1P1 (MOLT-4, JURKAT and CEM) did migrate. The S1P ligand induced T-ALL cells chemotaxis in concentrations up to 500 nM and induced fugetaxis in higher concentrations (1000–10000 nM) through interactions with S1P1. When S1P1 was specifically blocked by the W146 compound, S1P-induced migration at lower concentrations was reduced, whereas higher concentrations induced cell migration. Furthermore, we observed that S1P/S1P1 interactions induced ERK and AKT phosphorylation, and modulation of Rac1 activity. Responding T-ALL blasts also expressed S1P3 mRNA but blockage of this receptor did not modify migratory responses. Our results indicate that S1P is involved in the migration of T-ALL/LBL blasts, which is dependent on S1P1 expression. Moreover, S1P concentrations in the given microenvironment might induce dose-dependent chemotaxis or fugetaxis of T-ALL blasts.

Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation

“…Traditionally, S1P has been a promoter of chemotaxis for lymphocytes [ 107 ] and a pro-survival signal [ 108 ]. As there is little S1P within tissues, the bulk is found in circulation [ 109 ].…”

Fingolimod-Conjugated Charge-Altering Releasable Transporters Efficiently and Specifically Deliver mRNA to Lymphocytes In Vivo and In Vitro

“…For these studies, we compared luciferase expression with either CART-2 or its non-FTY720-conjugated analogue CART-1 in cell lines expressing or lacking the S1P1 receptor (Figure ). Specifically, the Jurkat and K562 cell lines were used as an S1P1-expressing cellular model, − and the CHO cell line was used as a model that naturally lacks expression for S1P1 (Figure S1). 4 h after treatment, mRNA expression was measured as relative bioluminescence of the cells treated with CART/mRNA complexes compared to cells treated with naked Fluc mRNA, which were used as negative controls.…”

Sphingosine-1-Phosphate Receptor 1 Is Involved in Non-Obese Diabetic Mouse Thymocyte Migration Disorders

“…Furthermore, our group showed that S1P induces chemotaxis and chemokinesis of T-cell acute lymphoblastic leukemia (T-ALL) blasts at 100 nM. By contrast, high concentrations of S1P (1000, 5000 and 10,000 nM) induce fugetaxis (or chemorepulsion) of the same cells [ 17 ]. It is thus conceivable that different thymocyte subpopulations present different sensitivity in migratory behavior under S1P stimulation, depending on the concentration and receptor expression, and that VLA-5 expression could differentially influence cell response in these conditions.…”

“…S1P1 is widely expressed, mainly in endothelial cells, brain, heart and immune cells [ 14 , 15 ]. S1P1 signaling in T cells suppresses proliferation and cytokine production and regulates cell migration [ 9 , 16 ], promoting chemotaxis or fugetaxis depending on the S1P concentration [ 17 ]. Accordingly, several studies demonstrate the essential role of S1P and S1P1 in cell migration and, mainly, in the egress of T cells from the thymus to peripheral lymphoid organs.…”