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Role of Sphingolipid Metabolism in Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 21103

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Special Issue Editor

Prof. Dr. Markus Gräler

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Guest Editor

Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
Interests: Sphingosine 1-phosphate (S1P) signaling in inflammation and sepsis; sphingolipidomics by liquid chromatography coupled to mass spectrometry (LC-MS/MS); sphingolipid metabolism and associated diseases

Special Issue Information

Dear Colleagues,

Sphingolipids are not only structural components of cell membranes and organelles, but also contribute to specific lipid signaling. Besides their role in common lipid storage diseases, recent findings revealed additional roles in many other pathologies, such as inflammation and sepsis, skeletal deformities, deafness, neurodegeneration, myocardial infarction, atherosclerosis, fibrosis, infertility, acute kidney injury, hypoxia, respiratory diseases, and cancer. Sphingosine 1-phosphate (S1P) is the simplest phospholipid in this family and transduces extracellular signals into cells by binding and activating five G-protein-coupled cell-surface receptors designated as S1PR1–5. Defects in the generation of S1P via de novo synthesis or the catabolism of complex sphingolipids, or impairment of its degradation via the S1P-lyase can result in diseases such as sphingosine phosphate lyase insufficiency syndrome (SPLIS), but may also be used clinically for the treatment of diseases like multiple sclerosis (MS). This Special Issue will highlight recent developments regarding the diverse roles of sphingolipids in human pathologies.

Prof. Dr. Markus Gräler
Guest Editor

Manuscript Submission Information

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Keywords

Lipid signaling
S1P-lyase
Sphingosine 1-phosphate
Sphingosine kinase
Sphingomyelin
Ceramide
S1P receptor

Published Papers (9 papers)

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Research

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19 pages, 1681 KiB

Open AccessArticle

The Impact of Sphingosine Kinases on Inflammation-Induced Cytokine Release and Vascular Endothelial Barrier Integrity

by Andreas V. Thuy, Christina-Maria Reimann, Anke C. Ziegler and Markus H. Gräler

Int. J. Mol. Sci. 2022, 23(21), 12848; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112848 - 25 Oct 2022

Cited by 2 | Viewed by 1453

Abstract

Sphingosine kinases type 1 and 2 (SphK1/2) are required for the production of the immune modulator sphingosine 1-phosphate (S1P). SphK1 deficient mice (SphK1^−/−) revealed 50% reduced S1P in plasma, while SphK2^−/− mice demonstrated 2–3 times increased S1P levels in plasma. Since plasma S1P is a potent inducer of vascular endothelial cell (VEC) barrier stability, we hypothesized that higher and lower levels of S1P in SphK2^−/− and SphK1^−/− mice, respectively, compared to wild type (wt) mice should translate into decreased and increased severity of induced systemic inflammation due to improved or damaged VEC barrier maintenance. To our surprise, both SphK1^−/− and SphK2^−/− mice showed improved survival rate and earlier recovery from inflammation-induced weight loss compared to wt mice. While no difference was observed in VEC barrier stability by monitoring Evans blue leakage into peripheral tissues, SphK1^−/− mice demonstrated a distinct delay and SphK2^−/− mice an improved resolution of early pro-inflammatory cytokine release in plasma. Ex vivo cell culture experiments demonstrated that bone marrow-derived dendritic cells (BMDC) generated from SphK1^−/− and SphK2^−/− mice responded with decreased interferon-γ (IFN-γ) production upon stimulation with lipopolysaccharides (LPS) compared to wt BMDC, while activation-induced cytokine expression of lymphocytes and macrophages was not majorly altered. Ex vivo stimulation of macrophages with IFN-γ resulted in increased cytokine release. These results suggest that SphK1/2 are involved in production and secretion of IFN-γ by DC. DC-derived IFN-γ subsequently stimulates the production and secretion of a large panel of inflammatory cytokines by macrophages, which belong to the main cytokine-releasing cells of the early innate immune response. Inhibitors of SphK1/2 may therefore be attractive targets to dampen the early cytokine response of macrophages as part of the innate immune response. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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18 pages, 3695 KiB

Open AccessArticle

Sphingosine-1-Phosphate (S1P) Lyase Inhibition Aggravates Atherosclerosis and Induces Plaque Rupture in ApoE^−/− Mice

by Petra Keul, Susann Peters, Karin von Wnuck Lipinski, Nathalie H. Schröder, Melissa K. Nowak, Dragos A. Duse, Amin Polzin, Sarah Weske, Markus H. Gräler and Bodo Levkau

Int. J. Mol. Sci. 2022, 23(17), 9606; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179606 - 24 Aug 2022

Cited by 4 | Viewed by 2047

Abstract

Altered plasma sphingosine-1-phosphate (S1P) concentrations are associated with clinical manifestations of atherosclerosis. However, whether long-term elevation of endogenous S1P is pro- or anti-atherogenic remains unclear. Here, we addressed the impact of permanently high S1P levels on atherosclerosis in cholesterol-fed apolipoprotein E-deficient (ApoE^−/−) mice over 12 weeks. This was achieved by pharmacological inhibition of the S1P-degrading enzyme S1P lyase with 4-deoxypyridoxine (DOP). DOP treatment dramatically accelerated atherosclerosis development, propagated predominantly unstable plaque phenotypes, and resulted in frequent plaque rupture with atherothrombosis. Macrophages from S1P lyase-inhibited or genetically deficient mice had a defect in cholesterol efflux to apolipoprotein A-I that was accompanied by profoundly downregulated cholesterol transporters ATP-binding cassette transporters ABCA1 and ABCG1. This was dependent on S1P signaling through S1PR3 and resulted in dramatically enhanced atherosclerosis in ApoE^−/−/S1PR3^−/− mice, where DOP treatment had no additional effect. Thus, high endogenous S1P levels promote atherosclerosis, compromise cholesterol efflux, and cause genuine plaque rupture. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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21 pages, 5959 KiB

Open AccessArticle

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

by Anabel S. De la Garza-Rodea, Steven A. Moore, Jesus Zamora-Pineda, Eric P. Hoffman, Karishma Mistry, Ashok Kumar, Jonathan B. Strober, Piming Zhao, Jung H. Suh and Julie D. Saba

Int. J. Mol. Sci. 2022, 23(14), 7579; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147579 - 08 Jul 2022

Cited by 1 | Viewed by 2037

Abstract

Duchenne muscular dystrophy (DMD) is a congenital myopathy caused by mutations in the dystrophin gene. DMD pathology is marked by myositis, muscle fiber degeneration, and eventual muscle replacement by fibrosis and adipose tissue. Satellite cells (SC) are muscle stem cells critical for muscle regeneration. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes SC proliferation, regulates lymphocyte trafficking, and is irreversibly degraded by sphingosine phosphate lyase (SPL). Here, we show that SPL is virtually absent in normal human and murine skeletal muscle but highly expressed in inflammatory infiltrates and degenerating fibers of dystrophic DMD muscle. In mdx mice that model DMD, high SPL expression is correlated with dysregulated S1P metabolism. Perinatal delivery of the SPL inhibitor LX2931 to mdx mice augmented muscle S1P and SC numbers, reduced leukocytes in peripheral blood and skeletal muscle, and attenuated muscle inflammation and degeneration. The effect on SC was also observed in SCID/mdx mice that lack mature T and B lymphocytes. Transcriptional profiling in the skeletal muscles of LX2931-treated vs. control mdx mice demonstrated changes in innate and adaptive immune functions, plasma membrane interactions with the extracellular matrix (ECM), and axon guidance, a known function of SC. Our cumulative findings suggest that by raising muscle S1P and simultaneously disrupting the chemotactic gradient required for lymphocyte egress, SPL inhibition exerts a combination of muscle-intrinsic and systemic effects that are beneficial in the context of muscular dystrophy. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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16 pages, 2809 KiB

Open AccessArticle

Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells

by Redona Hafizi, Faik Imeri, Bisera Stepanovska Tanturovska, Roxana Manaila, Stephanie Schwalm, Sandra Trautmann, Roland H. Wenger, Josef Pfeilschifter and Andrea Huwiler

Int. J. Mol. Sci. 2022, 23(11), 5882; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23115882 - 24 May 2022

Cited by 3 | Viewed by 2305

Abstract

Erythropoietin (Epo) is a crucial hormone regulating red blood cell number and consequently the hematocrit. Epo is mainly produced in the kidney by interstitial fibroblast-like cells. Previously, we have shown that in cultures of the immortalized mouse renal fibroblast-like cell line FAIK F3-5, sphingosine 1-phosphate (S1P), by activating S1P₁ and S1P₃ receptors, can stabilize hypoxia-inducible factor (HIF)-2α and upregulate Epo mRNA and protein synthesis. In this study, we have addressed the role of intracellular iS1P derived from sphingosine kinases (Sphk) 1 and 2 on Epo synthesis in F3-5 cells and in mouse primary cultures of renal fibroblasts. We show that stable knockdown of Sphk2 in F3-5 cells increases HIF-2α protein and Epo mRNA and protein levels, while Sphk1 knockdown leads to a reduction of hypoxia-stimulated HIF-2α and Epo protein. A similar effect was obtained using primary cultures of renal fibroblasts isolated from wildtype mice, Sphk1−/−, or Sphk2−/− mice. Furthermore, selective Sphk2 inhibitors mimicked the effect of genetic Sphk2 depletion and also upregulated HIF-2α and Epo protein levels. The combined blockade of Sphk1 and Sphk2, using Sphk2−/− renal fibroblasts treated with the Sphk1 inhibitor PF543, resulted in reduced HIF-2α and Epo compared to the untreated Sphk2−/− cells. Exogenous sphingosine (Sph) enhanced HIF-2α and Epo, and this was abolished by the combined treatment with the selective S1P₁ and S1P₃ antagonists NIBR-0213 and TY52156, suggesting that Sph was taken up by cells and converted to iS1P and exported to then act in an autocrine manner through S1P₁ and S1P₃. The upregulation of HIF-2α and Epo synthesis by Sphk2 knockdown was confirmed in the human hepatoma cell line Hep3B, which is well-established to upregulate Epo production under hypoxia. In summary, these data show that sphingolipids have diverse effects on Epo synthesis. While accumulation of intracellular Sph reduces Epo synthesis, iS1P will be exported to act through S1P₁₊₃ to enhance Epo synthesis. Furthermore, these data suggest that selective inhibition of Sphk2 is an attractive new option to enhance Epo synthesis and thereby to reduce anemia development in chronic kidney disease. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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23 pages, 4399 KiB

Open AccessArticle

Tumor Necrosis Factor-α Induces a Preeclamptic-like Phenotype in Placental Villi via Sphingosine Kinase 1 Activation

by Yuliya Fakhr, Saloni Koshti, Yasaman Bahojb Habibyan, Kirsten Webster and Denise G. Hemmings

Int. J. Mol. Sci. 2022, 23(7), 3750; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073750 - 29 Mar 2022

Cited by 7 | Viewed by 2526

Abstract

Preeclampsia (PE) involves inadequate placental function. This can occur due to elevated pro-inflammatory tumor necrosis factor-α (TNF-α). In other tissues, TNF-α signals via sphingosine kinase 1 (SphK1). SphK1 hinders syncytial formation. Whether this occurs downstream of TNF-α signaling is unclear. We hypothesized that placental SphK1 levels are higher in PE and elevated TNF-α decreases syncytial function, increases syncytial shedding, and increases cytokine/factor release via SphK1 activity. Term placental biopsies were analyzed for SphK1 using immunofluorescence and qRT-PCR. Term placental explants were treated after 4 days of culture, at the start of syncytial regeneration, with TNF-α and/or SphK1 inhibitors, PF-543. Syncytialization was assessed by measuring fusion and chorionic gonadotropin release. Cell death and shedding were measured by lactate dehydrogenase release and placental alkaline phosphatase-positive shed particles. Forty-two cytokines were measured using multiplex assays. Placental SphK1 was increased in PE. Increased cell death, shedding, interferon-α2, IFN-γ-induced protein 10, fibroblast growth factor 2, and platelet-derived growth factor-AA release induced by TNF-α were reversed upon SphK1 inhibition. TNF-α increased the release of 26 cytokines independently of SphK1. TNF-α decreased IL-10 release and inhibiting SphK1 reversed this effect. Inhibiting SphK1 alone decreased TNF-α release. Hence, SphK1 partially mediates the TNF-α-induced PE placental phenotype, primarily through cell damage, shedding, and specific cytokine release. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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19 pages, 2085 KiB

Open AccessArticle

Aβ-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears

by Michiel Van Bulck, Nicola Brandt, Ralf A. Claus, Markus Gräler and Anja U. Bräuer

Int. J. Mol. Sci. 2022, 23(4), 2300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042300 - 19 Feb 2022

Viewed by 1744

Abstract

Loss of active synapses and alterations in membrane lipids are crucial events in physiological aging as well as in neurodegenerative disorders. Both are related to the abnormal aggregation of amyloid-beta (Aβ) species, generally known as amyloidosis. There are two major known human Aβ species: Aβ_(1–40) and Aβ_(1–42). However, which of these species have more influence on active synapses and membrane lipids is still poorly understood. Additionally, the time-dependent effect of Aβ species on alterations in membrane lipids of hippocampal neurones and glial cells remains unknown. Therefore, our study contributes to a better understanding of the role of Aβ species in the loss of active synapses and the dysregulation of membrane lipids in vitro. We showed that Aβ_(1–40) or Aβ_(1–42) treatment influences membrane lipids before synaptic loss appears and that the loss of active synapses is not dependent on the Aβ species. Our lipidomic data analysis showed early changes in specific lipid classes such as sphingolipid and glycerophospholipid neurones. Our results underscore the potential role of lipids as a possible early diagnostic biomarker in amyloidosis-related disorders. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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24 pages, 3180 KiB

Open AccessArticle

T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model

by Khadija El-Hindi, Sebastian Brachtendorf, Jennifer Christina Hartel, Stephanie Oertel, Kerstin Birod, Nadine Merz, Sandra Trautmann, Dominique Thomas, Andreas Weigert, Tim J. Schäufele, Klaus Scholich, Susanne Schiffmann, Thomas Ulshöfer, Olaf Utermöhlen and Sabine Grösch

Int. J. Mol. Sci. 2022, 23(3), 1866; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031866 - 07 Feb 2022

Cited by 10 | Viewed by 2982

Abstract

To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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Review

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19 pages, 1690 KiB

Open AccessReview

Platelet-Derived S1P and Its Relevance for the Communication with Immune Cells in Multiple Human Diseases

by Céline Tolksdorf, Eileen Moritz, Robert Wolf, Ulrike Meyer, Sascha Marx, Sandra Bien-Möller, Ulrike Garscha, Gabriele Jedlitschky and Bernhard H. Rauch

Int. J. Mol. Sci. 2022, 23(18), 10278; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810278 - 07 Sep 2022

Cited by 4 | Viewed by 2054

Abstract

Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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22 pages, 1030 KiB

Open AccessReview

Keep a Little Fire Burning—The Delicate Balance of Targeting Sphingosine-1-Phosphate in Cancer Immunity

by Catherine Olesch, Bernhard Brüne and Andreas Weigert

Int. J. Mol. Sci. 2022, 23(3), 1289; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031289 - 24 Jan 2022

Cited by 3 | Viewed by 3105

Abstract

The sphingolipid sphingosine-1-phosphate (S1P) promotes tumor development through a variety of mechanisms including promoting proliferation, survival, and migration of cancer cells. Moreover, S1P emerged as an important regulator of tumor microenvironmental cell function by modulating, among other mechanisms, tumor angiogenesis. Therefore, S1P was proposed as a target for anti-tumor therapy. The clinical success of current cancer immunotherapy suggests that future anti-tumor therapy needs to consider its impact on the tumor-associated immune system. Hereby, S1P may have divergent effects. On the one hand, S1P gradients control leukocyte trafficking throughout the body, which is clinically exploited to suppress auto-immune reactions. On the other hand, S1P promotes pro-tumor activation of a diverse range of immune cells. In this review, we summarize the current literature describing the role of S1P in tumor-associated immunity, and we discuss strategies for how to target S1P for anti-tumor therapy without causing immune paralysis. Full article

(This article belongs to the Special Issue Role of Sphingolipid Metabolism in Human Diseases)

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