Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response

Fang, Victoria; Chaluvadi, Venkata; Ramos-Pérez, Willy D.; Mendoza, Alejandra; Baeyens, Audrey; Rivera, Richard; Chun, Jerold; Cammer, Michael; Schwab, Susan R.

doi:10.1038/ni.3619

Cited by 63 publications

(61 citation statements)

References 53 publications

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“…The roles of S1P–S1PR signalling in the induction of immune cell egress from lymphoid organs to the blood has been established 138 . Many studies suggest that sphingolipids also regulate the antitumour functions of various immune cell types.…”

Section: Sphingolipids and Cancer Therapymentioning

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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Section: Sphingolipids and Cancer Therapymentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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“…More recently, several papers reported a link between S1P/S1P kinases axis and Th17 25,26 . Here we report that turning on and off Shingosine kinases has a direct effect on IL-17 production.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine Kinases promote IL-17 expression in human T lymphocytes

Barra

Lepore²,

Gagliardi

et al. 2018

Sci Rep

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Sphingosine 1-phosphate (S1P) has a role in many cellular processes. S1P is involved in cell growth and apoptosis, regulation of cell trafficking, production of cytokines and chemokines. The kinases SphK1 and SphK2 (SphKs) phosphorilate Sphingosine (Sph) to S1P and several phosphatases revert S1P to sphingosine, thus assuring a balanced pool that can be depleted by a Sphingosine lyase in hexadecenal compounds and aldehydes. There are evidences that SphK1 and 2 may per se control cellular processes. Here, we report that Sph kinases regulate IL-17 expression in human T cells. SphKs inhibition impairs the production of IL-17, while their overexpression up-regulates expression of the cytokine through acetylation of IL-17 promoter. SphKs were up-regulated also in PBMCs of patients affected by IL-17 related diseases. Thus, S1P/S1P kinases axis is a mechanism likely to promote IL-17 expression in human T cells, representing a possible therapeutic target in human inflammatory diseases.

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“…S1P 5 , regulated by the expression of the transcription factor T‐BET, is critical for the egress of NK cells from the bone marrow and lymph nodes. NK cells can then return to these tissues via a mechanism that is dependent on CD62L expression . Differential gradients of S1P 5 and the S1P transporter SPNS2 on tissues, particularly lymphatic endothelial cells, combined with CXCR4 expression provide the spatial cues for NK cell localization in tissues .…”

Section: Immune Homeostasis At Mucosal Surfaces: Ilc Network In the Gutmentioning

confidence: 99%

“…NK cells can then return to these tissues via a mechanism that is dependent on CD62L expression . Differential gradients of S1P 5 and the S1P transporter SPNS2 on tissues, particularly lymphatic endothelial cells, combined with CXCR4 expression provide the spatial cues for NK cell localization in tissues . Although NK cells are found at relatively high frequency in the peripheral blood, they are most frequent in the nonlymphoid organs lung and liver and most abundant in the spleen .…”

Section: Immune Homeostasis At Mucosal Surfaces: Ilc Network In the Gutmentioning

confidence: 99%

Deconstructing deployment of the innate immune lymphocyte army for barrier homeostasis and protection

Almeida

Jacquelot

Belz

2018

Immunological Reviews

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Summary The study of the immune system has shifted from a purely dichotomous separation between the innate and adaptive arms to one that is now highly complex and reshaping our ideas of how steady‐state health is assured. It is now clear that immune cells do not neatly fit into these two streams and immune homeostasis depends on continual dialogue between multiple lineages of the innate (including dendritic cells, innate lymphoid cells, and unconventional lymphocytes) and adaptive (T and B lymphocytes) arms together with a finely tuned synergy between the host and microbes which is essential to ensure immune homeostasis. Innate lymphoid cells are critical players in this new landscape. Here, we discuss recent studies that have elucidated in detail the development of ILC s from their earliest progenitors and examine factors that influence their identification and ability to drive immune homeostasis and long‐term immune protection.

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Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response

Cited by 63 publications

References 53 publications

Sphingolipid metabolism in cancer signalling and therapy

Sphingolipid metabolism in cancer signalling and therapy

Sphingosine Kinases promote IL-17 expression in human T lymphocytes

Deconstructing deployment of the innate immune lymphocyte army for barrier homeostasis and protection

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