Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress

Zamora-Pineda, Jesus; Kumar, Ashok; Suh, Jung Hee; Zhang, Meng; Saba, Julie D.

doi:10.1084/jem.20160287

Cited by 46 publications

(67 citation statements)

References 50 publications

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“…More recently, conditional SPL KO mice have been developed that can be utilized to study the cell-type specific function of SPL in vivo (66). Investigating the function of SPL in the mice model will allow us to determine the importance of SPL during IAV infection in vivo.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN–Mediated Innate Immune Responses to Influenza A Virus Infection

Vijayan

Xia

Song

et al. 2017

The Journal of Immunology

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Sphingosine 1-phosphate (S1P) lyase (SPL) is an intracellular enzyme that mediates the irreversible degradation of the bioactive lipid, S1P. We have previously reported that overexpressed SPL displays anti-influenza viral activity; however the underlying mechanism is incompletely understood. In this study, we demonstrate that SPL functions as a positive regulator of IKKε to propel type I interferon (IFN)-mediated innate immune response against viral infection. Exogenous SPL expression inhibited influenza A virus (IAV) replication, which correlated with an increase in type I IFN production and interferon stimulated gene accumulation upon infection. In contrast, the lack of SPL expression led to an elevated cellular susceptibility to IAV infection. In support of this, SPL-deficient cells were defective in mounting an effective IFN response when stimulated by influenza viral RNAs. SPL augmented the activation status of IKKε, and enhanced the kinase-induced phosphorylation of IRF3 and synthesis of type I IFNs. However, S1P degradation-incompetent form of SPL also enhanced IFN responses, suggesting that SPL’s pro-IFN function is independent of S1P. Biochemical analysis revealed that SPL as well as the mutant form of SPL interact with IKKε. Importantly, when endogenous IKKε was down-regulated by an siRNA approach, SPL’s anti-influenza viral activity was markedly suppressed. This indicates that IKKε is crucial for SPL-mediated inhibition of influenza virus replication. Thus, the results illustrate the functional significance of the SPL-IKKε-IFN axis during host innate immunity against viral infection.

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Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN–Mediated Innate Immune Responses to Influenza A Virus Infection

Vijayan

Xia

Song

et al. 2017

The Journal of Immunology

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“…S1P is rapidly metabolized by S1P phosphatase (SGPP) 22 to sphingosine or by S1P lyase 1 (SPL; also known as SGPL1) 23 to yield ethanolamine-1-phosphate and hexadecanol (C16 fatty aldehyde) (FIG. 1).…”

Section: Sphingolipid Metabolism and Cancermentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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“…However a recent study by Zamora-Pineda et al 74 found that deletion of Sgpl in either TECs or thymic endothelial cells was not sufficient to cause a T-cell egress defect. In fact it was only the deletion of Sgpl in bone marrow-derived cells that resulted in reduced thymocyte egress and a concomitant intrathymic accumulation of mature SP thymocytes.…”

Section: Regulation Of S1p Levelsmentioning

confidence: 94%

“…TECs and endothelial cells have also been shown to express S1P lyase (Sgpl), an enzyme that degrades S1P to maintain low levels of S1P to regulate T‐cell egress. However a recent study by Zamora‐Pineda et al . found that deletion of Sgpl in either TECs or thymic endothelial cells was not sufficient to cause a T‐cell egress defect.…”

Section: The S1p–s1pr1 Axismentioning

confidence: 97%

“…found that deletion of Sgpl in either TECs or thymic endothelial cells was not sufficient to cause a T‐cell egress defect. In fact it was only the deletion of Sgpl in bone marrow‐derived cells that resulted in reduced thymocyte egress and a concomitant intrathymic accumulation of mature SP thymocytes . These bone‐marrow derived cells included DCs as well as T‐cells themselves, suggesting additional cell types beyond the thymic microenvironment that are able to influence thymocyte egress via the S1P–S1PR1 pathway …”

Section: The S1p–s1pr1 Axismentioning

confidence: 99%

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T-cell egress from the thymus: Should I stay or should I go?

James

Jenkinson

Anderson

2018

Journal of Leukocyte Biology

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T‐cells bearing the αβTCR play a vital role in defending the host against foreign pathogens and malignant transformation of self. Importantly, T‐cells are required to remain tolerant to the host's own cells and tissues in order to prevent self‐reactive responses that can lead to autoimmune disease. T‐cells achieve the capacity for self/nonself discrimination by undergoing a highly selective and rigorous developmental program during their maturation in the thymus. This organ is unique in its ability to support a program of T‐cell development that ensures the establishment of a functionally diverse αβTCR repertoire within the peripheral T‐cell pool. The thymus achieves this by virtue of specialized stromal microenvironments that contain heterogeneous cell types, whose organization and function underpins their ability to educate, support, and screen different thymocyte subsets through various stages of development. These stages range from the entry of early T‐cell progenitors into the thymus, through to the positive and negative selection of the αβTCR repertoire. The importance of the thymus medulla as a site for T‐cell tolerance and the exit of newly generated T‐cells into the periphery is well established. In this review, we summarize current knowledge on the developmental pathways that take place during αβT‐cell development in the thymus. In addition, we focus on the mechanisms that regulate thymic egress and contribute to the seeding of peripheral tissues with newly selected self‐tolerant αβT‐cells.

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Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress

Abstract: Saba and collaborators show that dendritic cells generate the thymic sphingosine-1-phosphate gradient and regulate T cell egress.

Cited by 46 publications

References 50 publications

Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN–Mediated Innate Immune Responses to Influenza A Virus Infection

Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN–Mediated Innate Immune Responses to Influenza A Virus Infection

Sphingolipid metabolism in cancer signalling and therapy

T-cell egress from the thymus: Should I stay or should I go?

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