Sandra Trautmann

Goethe University Frankfurt

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Dominique Thomas

Goethe University Frankfurt

Gerd Geißlinger

Fraunhofer Institute for Translational Medicine and Pharmacology

Yannick Schreiber

Fraunhofer Institute for Translational Medicine and Pharmacology

Lisa Hahnefeld

Fraunhofer Institute for Translational Medicine and Pharmacology

Irmgard Tegeder

Goethe University Frankfurt

Josef Pfeilschifter

Goethe University Frankfurt

Robert Gurke

Goethe University Frankfurt

Nerea Ferreirós

Goethe University Frankfurt

Carlo Angioni

Goethe University Frankfurt

Alexander Koch

RWTH Aachen University

Cooperative Institutions

Goethe University Frankfurt

158

University Hospital Frankfurt

108

Fraunhofer Institute for Translational Medicine and Pharmacology

Goethe Institute

Fraunhofer Institute for Molecular Biology and Applied Ecology

Medical University of Graz

Frankfurt Cancer Institute

Heidelberg University

Johannes Gutenberg University Mainz

Deutschen Konsortium für Translationale Krebsforschung

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Machine learning and biological validation identify sphingolipids as potential mediators of paclitaxel-induced neuropathy in cancer patients

medRxiv (Cold Spring Harbor Laboratory) (2023)

Jörn Lötsch Khayal Gasimli Sebastian Malkusch Lisa Hahnefeld Carlo Angioni

Abstract Background Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy. Methods High resolution mass spectrometry lipidomics was applied to quantify d = 255 different lipid mediators in the blood of n = 31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy. Results Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy. Conclusions Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects.

Sphingolipid

Chemotherapy-Induced Peripheral Neuropathy

10.1101/2023.10.08.23296716

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Preanalytical Biases in the Measurement of Human Blood Sphingolipids

International Journal of Molecular Sciences (2018)

Robert Brunkhorst Waltraud Pfeilschifter Sammy Patyna Stefan Büttner Timon Eckes

Dysregulation of blood sphingolipids is an emerging topic in clinical science. The objective of this study was to determine preanalytical biases that typically occur in clinical and translational studies and that influence measured blood sphingolipid levels. Therefore, we collected blood samples from four healthy male volunteers to investigate the effect of storage conditions (time, temperature, long-term storage, freeze⁻thaw cycles), blood drawing (venous or arterial sampling, prolonged venous compression), and sample preparation (centrifugation, freezing) on sphingolipid levels measured by LC-MS/MS. Our data show that sphingosine 1-phosphate (S1P) and sphinganine 1-phosphate (SA1P) were upregulated in whole blood samples in a time- and temperature-dependent manner. Increased centrifugation at higher speeds led to lower amounts of S1P and SA1P. All other preanalytical biases did not significantly alter the amounts of S1P and SA1P. Further, in almost all settings, we did not detect differences in (dihydro)ceramide levels. In summary, besides time-, temperature-, and centrifugation-dependent changes in S1P and SA1P levels, sphingolipids in blood remained stable under practically relevant preanalytical conditions.

Sphingolipid

Venous blood

Blood sampling

Blood collection

Human blood

10.3390/ijms19051390

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Citations (22)

High Glucosylceramides and Low Anandamide Contribute to Sensory Loss and Pain in Parkinson's Disease

Movement Disorders (2020)

Katharina Klatt‐Schreiner Lucie Valek Jun‐Suk Kang Alexander Khlebtovsky Sandra Trautmann

Abstract Background Parkinson's disease (PD) causes chronic pain in two‐thirds of patients, in part originating from sensory neuropathies. The aim of the present study was to describe the phenotype of PD‐associated sensory neuropathy and to evaluate its associations with lipid allostasis, the latter motivated by recent genetic studies associating mutations of glucocerebrosidase with PD onset and severity. Glucocerebrosidase catalyzes the metabolism of glucosylceramides. Methods We used quantitative sensory tests, pain ratings, and questionnaires and analyzed plasma levels of multiple bioactive lipid species using targeted lipidomic analyses. The study comprised 2 sets of patients and healthy controls: the first 128 Israeli PD patients and 224 young German healthy controls for exploration, the second 50/50 German PD patients and matched healthy controls for deeper analyses. Results The data showed a 70% prevalence of PD pain and sensory neuropathies with a predominant phenotype of thermal sensory loss plus mechanical hypersensitivity. Multivariate analyses of lipids revealed major differences between PD patients and healthy controls, mainly originating from glucosylceramides and endocannabinoids. Glucosylceramides were increased, whereas anandamide and lysophosphatidic acid 20:4 were reduced, stronger in patients with ongoing pain and with a linear relationship with pain intensity and sensory losses, particularly for glucosylceramide 18:1 and glucosylceramide 24:1. Conclusions Our data suggest that PD‐associated sensory neuropathies and PD pain are in part caused by accumulations of glucosylceramides, raising the intriguing possibility of reducing PD pain and sensory loss by glucocerebrosidase substituting or refolding approaches. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Anandamide

10.1002/mds.28186

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Citations (33)

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue

Journal of Allergy and Clinical Immunology (2019)

Thomas Bärnthaler Anna Theiler Diana Zabini Sandra Trautmann Elvira Stacher‐Priehse

Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E2 exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE2 metabolism under the control of TGF-β and microRNA 218.We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue.In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis.We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE2 levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE2 that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro.These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.

Ex vivo

Fibrocyte

10.1016/j.jaci.2019.11.032

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The Sphingosine Kinase-1 Activator, K6PC-5, Attenuates the Ebola Virus Infection and the Virus Induced Cell Death

SSRN Electronic Journal (2020)

Gergely Imre Verena Krähling Madeleine Eichler Sandra Trautmann Nerea Ferreirós

Ebola virus (EBOV) is responsible for outbreaks with case-fatality rates of up to 90% and for an epidemic in West Africa with more than ten thousand deaths. EBOV glycoprotein (EBOV-GP) is the only viral surface protein and is responsible for viral entry into cells. It has been suggested to play a role in the cytopathic effects induced by the virus. Here we uncover a critical role for sphingolipids in inhibiting viral entry and virus-mediated cytotoxicity. Sphingosine kinase 1 (SphK1) catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P). The administration of the SphK1 activator, K6PC-5, or S1P, or the overexpression of SphK1 consistently exhibited striking inhibitory effects in EBOV-GP-driven entry in EA.hy926 endothelial-like cells. Furthermore, K6PC-5 inhibited the subsequent necrotic cell death. Finally, K6PC-5 markedly reduced the EBOV titer in infected cells. These data present K6PC‑5 as efficient tool to inhibit EBOV infection in endothelial cells, and suggest further studies to evaluate its systemic effects.

Sphingosine Kinase

Sphingosine kinase 1

10.2139/ssrn.3652345

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Endothelial Sphingosine-1-Phosphate Receptor 4 Regulates Blood-Brain Barrier Permeability and Promotes a Homeostatic Endothelial Phenotype

Journal of Neuroscience (2021)

Lena Hansen Niklas Lohfink Rajkumar Vutukuri Roxane‐Isabelle Kestner Sandra Trautmann

The precise regulation of blood-brain barrier (BBB) permeability for immune cells and blood-borne substances is essential to maintain brain homeostasis. Sphingosine-1-phosphate (S1P), a lipid signaling molecule enriched in plasma, is known to affect BBB permeability. Previous studies focused on endothelial S1P receptors 1 and 2, reporting a barrier-protective effect of S1P1 and a barrier-disruptive effect of S1P2. Here, we present novel data characterizing the expression, localization, and function of the S1P receptor 4 (S1P4) on primary brain microvascular endothelial cells (BMECs). Hitherto, the receptor was deemed to be exclusively immune cell associated. We detected a robust expression of S1P4 in homeostatic murine BMECs (MBMECs), bovine BMECs (BBMECs), and porcine BMECs (PBMECs) and pinpointed its localization to abluminal endothelial membranes via immunoblotting of fractionated brain endothelial membrane fragments. Apical S1P treatment of BMECs tightened the endothelial barrier in vitro , whereas basolateral S1P treatment led to an increased permeability that correlated with S1P4 downregulation. Likewise, downregulation of S1P4 was observed in mouse brain microvessels (MBMVs) after stroke, a neurologic disease associated with BBB impairment. RNA sequencing and qPCR analysis of BMECs suggested the involvement of S1P4 in endothelial homeostasis and barrier function. Using S1P4 knock-out (KO) mice and S1P4 siRNA as well as pharmacological agonists and antagonists of S1P4 both in vitro and in vivo , we demonstrate an overall barrier-protective function of S1P4. We therefore suggest S1P4 as a novel target regulating BBB permeability and propose its therapeutic potential in CNS diseases associated with BBB dysfunction. SIGNIFICANCE STATEMENT Many neurologic diseases including multiple sclerosis and stroke are associated with blood-brain barrier (BBB) impairment and disturbed brain homeostasis. Sphingosine-1-phosphate receptors (S1PRs) are potent regulators of endothelial permeability and pharmacological S1PR modulators are already in clinical use. However, the precise role of S1P for BBB permeability regulation and the function of receptors other than S1P1 and S1P2 therein are still unclear. Our study shows both barrier-disruptive and barrier-protective effects of S1P at the BBB that depend on receptor polarization. We demonstrate the expression and novel barrier-protective function of S1P4 in brain endothelial cells and pinpoint its localization to abluminal membranes. Our work may contribute to the development of novel specific S1PR modulators for the treatment of neurologic diseases associated with BBB impairment.

Homeostasis

Barrier function

Sphingosine-1-phosphate receptor

S1PR1

Vascular permeability

10.1523/jneurosci.0188-21.2021

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A Sphingosine 1-Phosphate Gradient Is Linked to the Cerebral Recruitment of T Helper and Regulatory T Helper Cells during Acute Ischemic Stroke

International Journal of Molecular Sciences (2020)

Alexandra Lucaciu Hannah Kuhn Sandra Trautmann Nerea Ferreirós Helmuth Steinmetz

Emerging evidence suggests a complex relationship between sphingosine 1-phosphate (S1P) signaling and stroke. Here, we show the kinetics of S1P in the acute phase of ischemic stroke and highlight accompanying changes in immune cells and S1P receptors (S1PR). Using a C57BL/6 mouse model of middle cerebral artery occlusion (MCAO), we assessed S1P concentrations in the brain, plasma, and spleen. We found a steep S1P gradient from the spleen towards the brain. Results obtained by qPCR suggested that cells expressing the S1PR type 1 (S1P1+) were the predominant population deserting the spleen. Here, we report the cerebral recruitment of T helper (TH) and regulatory T (TREG) cells to the ipsilateral hemisphere, which was associated with differential regulation of cerebral S1PR expression patterns in the brain after MCAO. This study provides insight that the S1P-S1PR axis facilitates splenic T cell egress and is linked to the cerebral recruitment of S1PR+ TH and TREG cells. Further insights by which means the S1P-S1PR-axis orchestrates neuronal positioning may offer new therapeutic perspectives after ischemic stroke.

Sphingosine Kinase

Stroke

10.3390/ijms21176242

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Chemosensitivity of human colon cancer cells is influenced by a p53-dependent enhancement of ceramide synthase 5 and induction of autophagy

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (2018)

Sebastian Brachtendorf Ruth Anna Wanger Kerstin Birod Dominique Thomas Sandra Trautmann

Ceramide synthase

Sphingolipid

10.1016/j.bbalip.2018.07.011

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Citations (44)

Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells

Cellular and Molecular Life Sciences (2021)

Marthe-Susanna Wegner Nina Schömel Ellen M. Olzomer Sandra Trautmann Catherine Olesch

Hepatocellular carcinoma (HCC) is one of the most difficult cancer types to treat. Liver cancer is often diagnosed at late stages and therapeutic treatment is frequently accompanied by development of multidrug resistance. This leads to poor outcomes for cancer patients. Understanding the fundamental molecular mechanisms leading to liver cancer development is crucial for developing new therapeutic approaches, which are more efficient in treating cancer. Mice with a liver specific UDP-glucose ceramide glucosyltransferase (UGCG) knockout (KO) show delayed diethylnitrosamine (DEN)-induced liver tumor growth. Accordingly, the rationale for our study was to determine whether UGCG overexpression is sufficient to drive cancer phenotypes in liver cells. We investigated the effect of UGCG overexpression (OE) on normal murine liver (NMuLi) cells. Increased UGCG expression results in decreased mitochondrial respiration and glycolysis, which is reversible by treatment with EtDO-P4, an UGCG inhibitor. Furthermore, tumor markers such as FGF21 and EPCAM are lowered following UGCG OE, which could be related to glucosylceramide (GlcCer) and lactosylceramide (LacCer) accumulation in glycosphingolipid-enriched microdomains (GEMs) and subsequently altered signaling protein phosphorylation. These cellular processes lead to decreased proliferation in NMuLi/UGCG OE cells. Our data show that increased UGCG expression itself does not induce pro-cancerous processes in normal liver cells, which indicates that increased GlcCer expression leads to different outcomes in different cancer types.

Lactosylceramide

Liver Cancer

Glycosphingolipid

10.1007/s00018-021-03958-9

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Sapropterin (BH4) aggravates autoimmune encephalomyelitis in mice

Authorea (Authorea) (2020)

Katja Schmitz Sandra Trautmann Lisa Hahnefeld Caroline Fischer Robert Gurke

Background and Purpose: Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4) in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 medication (sapropterin) might increase the risk of autoimmune diseases. Experimental Approach: The present study assessed the implications for multiple sclerosis (MS) as a model autoimmune disease in MS patients and in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis in mice. Key Results: Plasma levels of biopterin were persistently low in MS patients, and the bypass product, neopterin tended to be increased suggesting a relative deficiency of BH4. Ex vivo stimulation of human whole blood indeed led to a drop of biopterin pointing to high consumption. Hence, BH4 replenishment might either further drive the immune response or beneficially restore the BH4 balance. To answer this question, mice were treated with sapropterin in the EAE model. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood, suggesting that BH4 facilitated the invasion of the central nervous system (CNS). Sapropterin-treated EAE mice had increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood brain barrier in EAE mice. Conclusion and Implications: Sapropterin might aggravate autoimmune disease of the CNS through permissive effects at the brain barrier.

Neopterin

Encephalomyelitis

Neuroimmunology

10.22541/au.159654458.85237036

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