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

Green, Jesse A.; Suzuki, Kazuhiro; Cho, Bryan; Willison, L. David; Palmer, Daniel; Allen, Christopher D.C.; Schmidt, Timothy H.; Xu, Ying; Proia, Richard L.; Coughlin, Shaun R.; Cyster, Jason G.

doi:10.1038/ni.2047

Cited by 236 publications

(294 citation statements)

References 51 publications

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“…Physiologically, insulin-mediated glycogen synthesis is diminished in response to S1P, suggesting that the sphingolipid mediator may contribute to hepatic insulin resistance keratinocytes via stimulation of the S1P 2 receptor subtype [14]. This is in accordance with a variety of studies indicating that S1P 2 inhibits proliferation in several cells such as mouse embryonic fibroblasts and germinal centre B cells [36,37]. The present study provides evidence that S1P 2 stimulation is able to attenuate insulin-dependent Akt phosphorylation.…”

Section: Discussionsupporting

confidence: 79%

“…Indeed, an inhibitory effect of the S1P/S1P 2 axis on Akt activation has been identified, especially in immune cells. It has been suggested that, by inhibiting Akt activation, S1P 2 helps to restrict germinal centre B cell survival and localisation to an S1P-low niche at the follicle centre [37]. Moreover, S1P has been shown to inhibit the endocytotic capacity of dendritic cells by S1P 2 receptor activation and Akt inactivation [21].…”

Section: Discussionmentioning

confidence: 99%

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Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

et al. 2013

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Aims/hypothesis Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance. Methods The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice. Results Palmitate induced an impressive formation of extraand intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P 2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P 2 , was not able to inhibit insulin signalling. Conclusions/interpretation These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P 2 receptor to impair insulin signalling. In particular, S1P 2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

et al. 2013

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“…The sphingosine-1-phosphate receptor S1PR2 helps to confi ne B cells to the GC ( 37 ). GC B cells showed the highest gene expression of S1pr2 .…”

Section: Cd35mentioning

confidence: 99%

Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

et al. 2014

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In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment infl uences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell traffi cking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli. SIGNIFICANCE: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma-leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor-stroma cross-talk. Cancer Discov; 4(12); 1448-65.

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“…In the current study, we demonstrated that P. chabaudi is capable of inducing an increase in plasma cells at 17 dpi, and depletion of IFN-g resulted in significantly increased plasma cell percentages in both NP-OVA control and P. chabaudi-and NP-OVA-injected mice. At present, it is unclear whether malaria modulates signals important to either the organization of the GC such as CXCL13 (62,63) or lymphocyte migration signals involving sphingosine 1-phosphate (64) that are critical to the GC reaction. The lack of detectable NP + cells in GCs following NP-OVA injection of P. chabaudi-infected mice, but the presence of NP-specific Ab suggests that the response to NP-OVA is extrafollicular during P. chabaudi infection.…”

Section: Discussionmentioning

confidence: 99%

Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

Wilmore

Maue

Lefebvre

et al. 2013

The Journal of Immunology

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High rates of coinfection occur in malaria endemic regions, leading to more severe disease outcomes. Understanding how coinfecting pathogens influence the immune system is important in the development of treatment strategies that reduce morbidity and mortality. Using the Plasmodium chabaudi mouse model of malaria and immunization with model Ags that are either T-dependent (4-hydroxy-3-nitrophenyl [NP]-OVA) or T-independent (NP-Ficoll), we analyzed the effects of acute malaria on the development of humoral immunity to secondary Ags. Total Ig and IgG1 NP–specific Ab responses to NP-OVA were significantly decreased in the P. chabaudi–infected group compared with the uninfected group, whereas NP-specific IgG2c Ab was significantly increased in the P. chabaudi–infected group. In contrast, following injection with T-independent NP-Ficoll, the P. chabaudi–infected group had significantly increased NP-specific total Ig, IgM, and IgG2c Ab titers compared with controls. Treatment with anti–IFN-γ led to an abrogation of the NP-specific IgG2c Ab induced by P. chabaudi infection but did not affect other NP-specific Ab isotypes or titers. IFN-γ depletion also increased the percentage of plasma cells in both P. chabaudi–infected and uninfected groups but decreased the percentage of B cells with a germinal center (GC) phenotype. Using immunofluorescent microscopy, we were able to detect NP+ GCs in the spleens of noninfected mice, but there were no detectible NP+ GCs in mice infected with P. chabaudi. These data suggest that during P. chabaudi infection, there is a shift toward an extrafollicular Ab response that could be responsible for decreased Ab responses to secondary T-dependent Ags.

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

Cited by 236 publications

References 51 publications

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

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