TY - JOUR A1 - Becker, Katrin Anne A1 - Riethmueller, Joachim A1 - Seitz, Aaron P. A1 - Gardner, Aaron A1 - Boudreau, Ryan A1 - Kamler, Markus A1 - Kleuser, Burkhard A1 - Schuchman, Edward A1 - Caldwell, Charles C. A1 - Edwards, Michael J. A1 - Grassme, Heike A1 - Brodlie, Malcolm A1 - Gulbins, Erich T1 - Sphingolipids as targets for inhalation treatment of cystic fibrosis JF - Advanced drug delivery reviews N2 - Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of beta 1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of beta 1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation. KW - Ceramide KW - Acid sphingomyelinase KW - Cystic fibrosis KW - COPD KW - Inhalation Y1 - 2018 U6 - https://doi.org/10.1016/j.addr.2018.04.015 SN - 0169-409X SN - 1872-8294 VL - 133 SP - 66 EP - 75 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Gulbins, Erich A1 - Palmada, Monica A1 - Reichel, Martin A1 - Lueth, Anja A1 - Boehmer, Christoph A1 - Amato, Davide A1 - Mueller, Christian P. A1 - Tischbirek, Carsten H. A1 - Groemer, Teja W. A1 - Tabatabai, Ghazaleh A1 - Becker, Katrin Anne A1 - Tripal, Philipp A1 - Staedtler, Sven A1 - Ackermann, Teresa F. A1 - van Brederode, Johannes A1 - Alzheimer, Christian A1 - Weller, Michael A1 - Lang, Undine E. A1 - Kleuser, Burkhard A1 - Grassme, Heike A1 - Kornhuber, Johannes T1 - Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs JF - Nature medicine N2 - Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants. Y1 - 2013 U6 - https://doi.org/10.1038/nm.3214 SN - 1078-8956 VL - 19 IS - 7 SP - 934 EP - + PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Reichel, Martin A1 - Hoenig, Stefanie A1 - Liebisch, Gerhard A1 - Lüth, Anja A1 - Kleuser, Burkhard A1 - Gulbins, Erich A1 - Schmitz, Gerd A1 - Kornhuber, Johannes T1 - Alterations of plasma glycerophospholipid and sphingolipid species in male alcohol-dependent patients JF - Biochimica et biophysica acta : Molecular and cell biology of lipids N2 - Background: Alcohol abuse is a major risk factor for somatic and neuropsychiatric diseases. Despite their potential clinical importance, little is known about the alterations of plasma glycerophospholipid (GPL) and sphingolipid (SPL) species associated with alcohol abuse. Methods: Plasma GPL and SPL species were quantified using electrospray ionization tandem mass spectrometry in samples from 23 male alcohol-dependent patients before and after detoxification, as well as from 20 healthy male controls. Results: A comparison of alcohol-dependent patients with controls revealed higher phosphatidylcholine (PC; P-value = 0.008) and phosphatidylinositol (PI; P-value = 0.001) concentrations in patients before detoxification, and higher PI (P-value = 0.001) and phosphatidylethanolamine (PE)-based plasmalogen (PEP; P-value = 0.003) concentrations after detoxification. Lysophosphatidylcholines (LPC) were increased by acute intoxication (P-value = 0.002). Sphingomyelin (SM) concentration increased during detoxification (P-value = 0.011). The concentration of SM 23:0 was lower in patients (P-value = 2.79 x 10(-5)), and the concentrations of ceramide Cer d18:1/16:0 and Cer d18:1/18:0 were higher in patients (P-value = 2.45 x 10(-5) and 3.73 x 10(-5)). Activity of lysosomal acid sphingomyelinase (ASM) in patients correlated positively with the concentrations of eight LPC species, while activity of secreted ASM was inversely correlated with several PE, PI and PC species, and positively correlated with the molar ratio of PC to SM (Pearson's r = 0.432; P-value = 0.039). Conclusion: Plasma concentrations of numerous GPL and SPL species were altered in alcohol-dependent patients. These molecules might serve as potential biomarkers to improve the diagnosis of patients and to indicate health risks associated with alcohol abuse. Our study further indicates that there are strong interactions between plasma GPL concentrations and SPL metabolism. (C) 2015 Elsevier B.V. All rights reserved. KW - Acid sphingomyelinase KW - Alcohol dependence KW - Anxiety KW - Cardiovascular KW - Case-control study KW - Ceramide KW - Clinical KW - Depression KW - Diagnostic KW - Disease KW - Glycerophospholipids KW - Lysophosphatidylcholines KW - Mass spectrometry KW - Phosphatidylcholines KW - Phosphatidylinositols KW - Plasma KW - Plasmalogens KW - Sphingolipids KW - Sphingomyelin KW - Tandem mass spectrometry Y1 - 2015 U6 - https://doi.org/10.1016/j.bbalip.2015.08.005 SN - 1388-1981 SN - 0006-3002 VL - 1851 IS - 11 SP - 1501 EP - 1510 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Pewzner-Jung, Yael A1 - Tabazavareh, Shaghayegh Tavakoli A1 - Grassme, Heike A1 - Becker, Katrin Anne A1 - Japtok, Lukasz A1 - Steinmann, Joerg A1 - Joseph, Tammar A1 - Lang, Stephan A1 - Tuemmler, Burkhard A1 - Schuchman, Edward H. A1 - Lentsch, Alex B. A1 - Kleuser, Burkhard A1 - Edwards, Michael J. A1 - Futerman, Anthony H. A1 - Gulbins, Erich T1 - Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa JF - EMBO molecular medicine N2 - Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P.aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P.aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection. KW - cystic fibrosis KW - long chain base KW - lung infection KW - Pseudomonas aeruginosa KW - sphingosine Y1 - 2014 U6 - https://doi.org/10.15252/emmm.201404075 SN - 1757-4676 SN - 1757-4684 VL - 6 IS - 9 SP - 1205 EP - 1214 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Henry, Brian D. A1 - Neill, Daniel R. A1 - Becker, Katrin Anne A1 - Gore, Suzanna A1 - Bricio-Moreno, Laura A1 - Ziobro, Regan A1 - Edwards, Michael J. A1 - Muehlemann, Kathrin A1 - Steinmann, Joerg A1 - Kleuser, Burkhard A1 - Japtok, Lukasz A1 - Luginbuehl, Miriam A1 - Wolfmeier, Heidi A1 - Scherag, Andre A1 - Gulbins, Erich A1 - Kadioglu, Aras A1 - Draeger, Annette A1 - Babiychuk, Eduard B. T1 - Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice JF - Nature biotechnology : the science and business of biotechnology N2 - Gram-positive bacterial pathogens that secrete cytotoxic pore-forming toxins, such as Staphylococcus aureus and Streptococcus pneumoniae, cause a substantial burden of disease. Inspired by the principles that govern natural toxin-host interactions, we have engineered artificial liposomes that are tailored to effectively compete with host cells for toxin binding. Liposome-bound toxins are unable to lyse mammalian cells in vitro. We use these artificial liposomes as decoy targets to sequester bacterial toxins that are produced during active infection in vivo. Administration of artificial liposomes within 10 h after infection rescues mice from septicemia caused by S. aureus and S. pneumoniae, whereas untreated mice die within 24-33 h. Furthermore, liposomes protect mice against invasive pneumococcal pneumonia. Composed exclusively of naturally occurring lipids, tailored liposomes are not bactericidal and could be used therapeutically either alone or in conjunction with antibiotics to combat bacterial infections and to minimize toxin-induced tissue damage that occurs during bacterial clearance. Y1 - 2015 U6 - https://doi.org/10.1038/nbt.3037 SN - 1087-0156 SN - 1546-1696 VL - 33 IS - 1 SP - 81 EP - U295 PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Carpinteiro, Alexander A1 - Becker, Katrin Anne A1 - Japtok, Lukasz A1 - Hessler, Gabriele A1 - Keitsch, Simone A1 - Pozgajova, Miroslava A1 - Schmid, Kurt W. A1 - Adams, Constantin A1 - Müller, Stefan A1 - Kleuser, Burkhard A1 - Edwards, Michael J. A1 - Grassme, Heike A1 - Helfrich, Iris A1 - Gulbins, Erich T1 - Regulation of hematogenous tumor metastasis by acid sphingomyelinase JF - EMBO molecular medicine N2 - Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of 51 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C-16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing 1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis. KW - acid sphingomyelinase KW - ceramide KW - integrins KW - platelets KW - tumor-metastasis Y1 - 2015 SN - 1757-4676 SN - 1757-4684 VL - 7 IS - 6 SP - 714 EP - 734 PB - Wiley-Blackwell CY - Hoboken ER - TY - GEN A1 - Reichel, Martin A1 - Rhein, Cosima A1 - Hofmann, Lena M. A1 - Monti, Juliana A1 - Japtok, Lukasz A1 - Langgartner, Dominik A1 - Füchsl, Andrea M. A1 - Kleuser, Burkhard A1 - Gulbins, Erich A1 - Hellerbrand, Claus A1 - Reber, Stefan O. A1 - Kornhuber, Johannes T1 - Chronic psychosocial stress in mice is associated with increased acid sphingomyelinase activity in liver and serum and with hepatic C16:0-ceramide accumulation T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28% (P = 0.006) and secretory Asm activity by 47% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-alpha (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1120 KW - chronic psychosocial stress KW - acid sphingomyelinase KW - ceramide KW - sphingolipid metabolism KW - chronic subordinate colony housing (CSC) KW - liver metabolism Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-446241 SN - 1866-8372 IS - 1120 ER - TY - GEN A1 - Nojima, Hiroyuki A1 - Konishi, Takanori A1 - Freeman, Christopher M. A1 - Schuster, Rebecca M. A1 - Japtok, Lukasz A1 - Kleuser, Burkhard A1 - Edwards, Michael J. A1 - Gulbins, Erich A1 - Lentsch, Alex B. T1 - Chemokine receptors, CXCR1 and CXCR2, differentially regulate exosome release in hepatocytes T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 538 KW - hepatic ischemia-reperfusion KW - liver-regeneration KW - injury KW - ischemia/reperfusion KW - neutrophil KW - ceramide KW - homolog KW - mice KW - mechanisms KW - recovery Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-410885 SN - 1866-8372 IS - 538 ER - TY - JOUR A1 - Huston, Joseph P. A1 - Kornhuber, Johannes A1 - Muehle, Christiane A1 - Japtok, Lukasz A1 - Komorowski, Mara A1 - Mattern, Claudia A1 - Reichel, Martin A1 - Gulbins, Erich A1 - Kleuser, Burkhard A1 - Topic, Bianca A1 - Silva, Maria A. De Souza A1 - Mueller, Christian P. T1 - A sphingolipid mechanism for behavioral extinction JF - Journal of neurochemistry N2 - Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions. KW - acid sphingomyelinase KW - ceramide KW - extinction KW - hippocampus KW - operant behavior KW - sphingomyelin Y1 - 2016 U6 - https://doi.org/10.1111/jnc.13537 SN - 0022-3042 SN - 1471-4159 VL - 137 SP - 589 EP - 603 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Hollmann, Claudia A1 - Werner, Sandra A1 - Avota, Elita A1 - Reuter, Dajana A1 - Japtok, Lukasz A1 - Kleuser, Burkhard A1 - Gulbins, Erich A1 - Becker, Katrin Anne A1 - Schneider-Schaulies, Jürgen A1 - Beyersdorf, Niklas T1 - Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4(+) Conventional versus Foxp3(+) Regulatory T Cells JF - The journal of immunology N2 - CD4(+) Foxp3(+) regulatory T cells (Tregs) depend on CD28 signaling for their survival and function, a receptor that has been previously shown to activate the acid sphingomyelinase (Asm)/ceramide system. In this article, we show that the basal and CD28-induced Asm activity is higher in Tregs than in conventional CD4(+) T cells (Tconvs) of wild-type (wt) mice. In Asm-deficient (Smpd1(-/-); Asm(-/-)) mice, as compared with wt mice, the frequency of Tregs among CD4(+) T cells, turnover of the effector molecule CTLA-4, and their suppressive activity in vitro were increased. The biological significance of these findings was confirmed in our Treg-sensitive mouse model of measles virus (MV) CNS infection, in which we observed more infected neurons and less MV-specific CD8(+) T cells in brains of Asm(-/-) mice compared with wt mice. In addition to genetic deficiency, treatment of wt mice with the Asm inhibitor amitriptyline recapitulated the phenotype of Asm-deficient mice because it also increased the frequency of Tregs among CD4(+) T cells. Reduced absolute cell numbers of Tconvs after inhibitor treatment in vivo and extensive in vitro experiments revealed that Tregs are more resistant toward Asm inhibitor-induced cell death than Tconvs. Mechanistically, IL-2 was capable of providing crucial survival signals to the Tregs upon inhibitor treatment in vitro, shifting the Treg/Tconv ratio to the Treg side. Thus, our data indicate that Asm-inhibiting drugs should be further evaluated for the therapy of inflammatory and autoimmune disorders. Y1 - 2016 U6 - https://doi.org/10.4049/jimmunol.1600691 SN - 0022-1767 SN - 1550-6606 VL - 197 SP - 3130 EP - 3141 PB - American Assoc. of Immunologists CY - Bethesda ER -