scholarly journals Erythrocytes increase endogenous sphingosine 1-phosphate (S1P) levels as an adaptive response to SARS-CoV-2 infection

2021 ◽  
Author(s):  
Martin Sebastian Winkler ◽  
Ralf A Claus ◽  
Mareike Schilder ◽  
Stefan Pöhlmann ◽  
Sina Coldewey ◽  
...  
Keyword(s):  
Cell Culture ◽  
Blood Cells ◽  
Adaptive Response ◽  
Kinase Activity ◽  
Density Lipoprotein ◽  
Sphingosine Kinase ◽  
Healthy Controls ◽  
Sphingosine Kinase 1 ◽  
Adaptive Mechanisms ◽  
Sphingosine 1 Phosphate

Low plasma levels of the signaling lipid metabolite sphingosine 1-phosphate (S1P) are associated with disrupted endothelial cell barriers, lymphopenia and reduced responsivity to hypoxia. Total S1P levels were also reduced in 23 critically ill patients with coronavirus disease 2019 (COVID-19), and the two main S1P carrier serum albumin (SA) and high-density lipoprotein (HDL) were dramatically low. Surprisingly, we observed a carrier changing shift from SA to HDL, which probably prevented an even further drop of S1P levels. Furthermore, intracellular S1P levels in red blood cells (RBC) were significantly increased in COVID-19 patients compared to healthy controls due to upregulation of S1P producing sphingosine kinase 1 and downregulation of S1P degrading lyase expression. Cell culture experiments supported increased sphingosine kinase activity and unchanged S1P release from RBC stores of COVID-19 patients. These observations suggest adaptive mechanisms for maintenance of the vasculature and immunity as well as prevention of tissue hypoxia in COVID-19 patients.

scholarly journals Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

2004 ◽  
Vol 279 (50) ◽  
pp. 52487-52492 ◽  
Author(s):  
Maria L. Allende ◽  
Teiji Sasaki ◽  
Hiromichi Kawai ◽  
Ana Olivera ◽  
Yide Mi ◽  
...  
Keyword(s):  
Vascular Development ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Cellular Functions ◽  
Lymphocyte Trafficking ◽  
Signaling Molecule ◽  
Physiological Functions ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations

Hypertension ◽  
2021 ◽  
Author(s):  
Jiujiang Liao ◽  
Yangxi Zheng ◽  
Mingyu Hu ◽  
Ping Xu ◽  
Li Lin ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Sphingosine Kinase ◽  
Actin Dynamics ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Sphingosine Kinase 1 ◽  
Sphingosine 1 Phosphate

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized trophoblast cells) cell invasion in a Hippo-signaling–dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA/ROCK induced actin polymerization. Mutation-based YAP-5SA demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

scholarly journals Overexpression of Sphingosine Kinase-1 and Sphingosine-1-Phosphate Receptor-3 in Severe Plasmodium falciparum Malaria with Pulmonary Edema

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Parnpen Viriyavejakul ◽  
Chuchard Punsawad
Keyword(s):  
Plasmodium Falciparum ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Sphingosine Kinase ◽  
Alveolar Epithelial Cells ◽  
Sphingosine Kinase 1 ◽  
Expression Levels ◽  
Alveolar Epithelial ◽  
Sphingosine 1 Phosphate

Pulmonary edema (PE) is a major cause of pulmonary manifestations of severe Plasmodium falciparum malaria and is usually associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The sphingosine kinase-1 (SphK-1)/sphingosine-1-phosphate receptor-3 (S1PR-3) pathway has recently been reported to affect the pathogenesis of lung injury, but the expression of these proteins in the lungs of severe P. falciparum malaria patients has not been investigated. The cellular expression of SphK-1 and S1PR-3 in lung tissues from autopsied patients with P. falciparum malaria was investigated using immunohistochemistry (IHC). Lung tissues from patients who died of severe P. falciparum malaria were classified into two groups based on histopathological findings: those with PE (18 patients) and those without PE (non-PE, 19 patients). Ten samples of normal lung tissues were used as the control group. The protein expression levels of SphK-1 and S1PR-3 were significantly upregulated in endothelial cells (ECs), alveolar epithelial cells, and alveolar macrophages (AMs) in the lungs of severe P. falciparum malaria patients with PE compared to those in the non-PE and control groups (all p<0.001). In addition, the SphK-1 and S1PR-3 expression levels were significantly positively correlated in pulmonary ECs (rs=0.922, p<0.001), alveolar epithelial cells (rs=0.995, p<0.001), and AMs (rs=0.969, p<0.001). In conclusion, both the SphK-1 and S1PR-3 proteins were overexpressed in the lung tissues of severe P. falciparum malaria patients with PE, suggesting that SphK-1 and S1PR-3 mediate the pathogenesis of PE in severe malaria. Targeting the regulation of SphK-1 and/or S1PR-3 may be an approach to treat pulmonary complications in severe P. falciparum patients.

scholarly journals Early Activation of Sphingosine Kinase in Mast Cells and Recruitment to FcεRI Are Mediated by Its Interaction with Lyn Kinase

2004 ◽  
Vol 24 (19) ◽  
pp. 8765-8777 ◽  
Author(s):  
Nicole Urtz ◽  
Ana Olivera ◽  
Elisa Bofill-Cardona ◽  
Robert Csonga ◽  
Andreas Billich ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Immunoglobulin E ◽  
Sphingosine Kinase ◽  
Lipid Kinase ◽  
Lyn Kinase ◽  
Sphingosine 1 Phosphate ◽  
High Affinity Receptor

ABSTRACT Sphingosine kinase has been recognized as an essential signaling molecule that mediates the intracellular conversion of sphingosine to sphingosine-1-phosphate. In mast cells, induction of sphingosine kinase and generation of sphingosine-1-phosphate have been linked to the initial rise in Ca2+, released from internal stores, and to degranulation. These events either precede or are concomitant with the activation of phospholipase C-γ and the generation of inositol trisphosphate. Here we show that sphingosine kinase type 1 (SPHK1) interacts directly with the tyrosine kinase Lyn and that this interaction leads to the recruitment of this lipid kinase to the high-affinity receptor for immunoglobulin E (FcεRI). The interaction of SPHK1 with Lyn caused enhanced lipid and tyrosine kinase activity. After FcεRI triggering, enhanced sphingosine kinase activity was associated with FcεRI in sphingolipid-enriched rafts of mast cells. Bone marrow-derived mast cells from Lyn−/ − mice, compared to syngeneic wild-type cells, were defective in the initial induction of SPHK1 activity, and the defect was overcome by retroviral Lyn expression. These findings position the activation of SPHK1 as an FcεRI proximal event.

scholarly journals Intracellular localization of sphingosine kinase 1 alters access to substrate pools but does not affect the degradative fate of sphingosine-1-phosphate

2010 ◽  
Vol 51 (9) ◽  
pp. 2546-2559 ◽  
Author(s):  
Deanna L. Siow ◽  
Charles D. Anderson ◽  
Evgeny V. Berdyshev ◽  
Anastasia Skobeleva ◽  
Stuart M. Pitson ◽  
...  
Keyword(s):  
Intracellular Localization ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Sphingosine 1 Phosphate

Sphingosine 1-phosphate signalling in cancer

2012 ◽  
Vol 40 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Nigel J. Pyne ◽  
Francesca Tonelli ◽  
Keng Gat Lim ◽  
Jaclyn S. Long ◽  
Joanne Edwards ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
Receptor Expression ◽  
Sphingosine Kinase 1 ◽  
Histone Deacetylase 1 ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

There is an increasing body of evidence demonstrating a critical role for the bioactive lipid S1P (sphingosine 1-phosphate) in cancer. S1P is synthesized and metabolized by a number of enzymes, including sphingosine kinase, S1P lyase and S1P phosphatases. S1P binds to cell-surface G-protein-coupled receptors (S1P1–S1P5) to elicit cell responses and can also regulate, by direct binding, a number of intracellular targets such as HDAC (histone deacetylase) 1/2 to induce epigenetic regulation. S1P is involved in cancer progression including cell transformation/oncogenesis, cell survival/apoptosis, cell migration/metastasis and tumour microenvironment neovascularization. In the present paper, we describe our research findings regarding the correlation of sphingosine kinase 1 and S1P receptor expression in tumours with clinical outcome and we define some of the molecular mechanisms underlying the involvement of sphingosine kinase 1 and S1P receptors in the formation of a cancer cell migratory phenotype. The role of sphingosine kinase 1 in the acquisition of chemotherapeutic resistance and the interaction of S1P receptors with oncogenes such as HER2 is also reviewed. We also discuss novel aspects of the use of small-molecule inhibitors of sphingosine kinase 1 in terms of allosterism, ubiquitin–proteasomal degradation of sphingosine kinase 1 and anticancer activity. Finally, we describe how S1P receptor-modulating agents abrogate S1P receptor–receptor tyrosine kinase interactions, with potential to inhibit growth-factor-dependent cancer progression.

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