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The sphingosine 1-phosphate receptor S1P? maintains the homeostasis of germinal center B cells and promotes niche confinement.

ABSTRACT: Mice deficient in sphingosine 1-phosphate receptor type 2 (S1P(2)) develop diffuse large B cell lymphoma. However, the role of S1P(2) in normal germinal center (GC) physiology is unknown. Here we show that S1P(2)-deficient GC B cells outgrew their wild-type counterparts in chronically established GCs. We found that antagonism of the kinase Akt mediated by S1P(2) and its downstream mediators G?(12), G?(13) and p115RhoGEF regulated cell viability and was required for growth control in chronically proliferating GCs. Moreover, S1P(2) inhibited GC B cell responses to follicular chemoattractants and helped confine cells to the GC. In addition, S1P(2) overexpression promoted the centering of activated B cells in the follicle. We suggest that by inhibiting Akt activation and migration, S1P(2) helps restrict GC B cell survival and localization to an S1P-low niche at the follicle center.

SUBMITTER: Green JA

PROVIDER: S-EPMC3158008 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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The sphingosine 1-phosphate receptor S1P₂ maintains the homeostasis of germinal center B cells and promotes niche confinement.

Green Jesse A JA Suzuki Kazuhiro K Cho Bryan B Willison L David LD Palmer Daniel D Allen Christopher D C CD Schmidt Timothy H TH Xu Ying Y Proia Richard L RL Coughlin Shaun R SR Cyster Jason G JG

Nature immunology 20110605 7

Mice deficient in sphingosine 1-phosphate receptor type 2 (S1P(2)) develop diffuse large B cell lymphoma. However, the role of S1P(2) in normal germinal center (GC) physiology is unknown. Here we show that S1P(2)-deficient GC B cells outgrew their wild-type counterparts in chronically established GCs. We found that antagonism of the kinase Akt mediated by S1P(2) and its downstream mediators Gα(12), Gα(13) and p115RhoGEF regulated cell viability and was required for growth control in chronically ...[more]

PMID: 21642988

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Project description:Because sphingosine 1-phosphate (S1P) is a potent stimulator of angiogenesis, we hypothesized that the S1P pathway is activated to stimulate endometrial/placental angiogenesis during pregnancy. We initially localized S1P signaling pathway members in the gravid and nongravid uterine horns of unilaterally pregnant ewes. Sphingosine kinase-1 expression was greater in gravid compared to nongravid horns. In situ hybridization revealed elevated expression of sphingosine 1-phosphate phosphatase (SGPP1) in gravid interplacentomal endometrial stroma on Days 20 and 40 compared to the nongravid uterine horn, but expression increased in endometrium of the nongravid uterine horn between Days 40 and 120. SGPP1 expression increased in placentomes late in gestation. Sphingosine 1-phosphate lyase mRNA was modestly expressed at Day 20 and then decreased. In contrast, sphingosine 1-phosphate receptor 1 (S1PR1) mRNA increased in endometrium and caruncular stroma of the gravid uterine horn. Treatment with FTY720 and VPC23019, S1P receptor antagonists, blocked human and ovine endothelial cell invasion using an in vitro model of sprouting angiogenesis. Knockdown of S1PR1 with siRNA reduced invasion responses as well. We previously reported that delta-like 4 (DLL4) and A disintegrin and metalloproteinase with thrombospondin-like repeats 1 (ADAMTS1) participate in endothelial cell invasion stimulated by S1P and growth factors in vitro, and thus investigated whether their expression correlated with areas undergoing angiogenesis in vivo. DLL4 expression was similar to S1PR1, while ADAMTS1 mRNA was expressed by endometria of both nongravid and gravid horns, as well as conceptus and placentomes. These results establish that S1P signaling pathway members and S1P- and growth factor-regulated genes are prominent in uterine and placental tissue and in some cases are correlated with areas undergoing angiogenesis. Thus, S1P signaling may be crucial for proper fetal-placental development.

Dataset Information

The sphingosine 1-phosphate receptor S1P? maintains the homeostasis of germinal center B cells and promotes niche confinement.

Publications

The sphingosine 1-phosphate receptor S1P₂ maintains the homeostasis of germinal center B cells and promotes niche confinement.

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