@article{HustonKornhuberMuehleetal.2016, author = {Huston, Joseph P. and Kornhuber, Johannes and Muehle, Christiane and Japtok, Lukasz and Komorowski, Mara and Mattern, Claudia and Reichel, Martin and Gulbins, Erich and Kleuser, Burkhard and Topic, Bianca and Silva, Maria A. De Souza and Mueller, Christian P.}, title = {A sphingolipid mechanism for behavioral extinction}, series = {Journal of neurochemistry}, volume = {137}, journal = {Journal of neurochemistry}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {0022-3042}, doi = {10.1111/jnc.13537}, pages = {589 -- 603}, year = {2016}, abstract = {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.}, language = {en} } @article{ZeitlerYeAndreyevaetal.2019, author = {Zeitler, Stefanie and Ye, Lian and Andreyeva, Aksana and Schumacher, Fabian and Monti, Juliana and N{\"u}rnberg, Bernd and Nowak, Gabriel and Kleuser, Burkhard and Reichel, Martin and Fejtova, Anna and Kornhuber, Johannes and Rhein, Cosima and Friedland, Kristina}, title = {Acid sphingomyelinase - a regulator of canonical transient receptor potential channel 6 (TRPC6) activity}, series = {Journal of neurochemistry}, volume = {150}, journal = {Journal of neurochemistry}, number = {6}, publisher = {Wiley}, address = {Hoboken}, issn = {0022-3042}, doi = {10.1111/jnc.14823}, pages = {678 -- 690}, year = {2019}, abstract = {Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM-induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non-selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John's wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin-induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6-mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration-related way. This effect was confirmed in whole-cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin-1-positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine-tuning their physical properties.}, language = {en} } @article{BeckmannBeckerKadowetal.2019, author = {Beckmann, Nadine and Becker, Katrin Anne and Kadow, Stephanie and Schumacher, Fabian and Kramer, Melanie and Kuehn, Claudine and Schulz-Schaeffer, Walter J. and Edwards, Michael J. and Kleuser, Burkhard and Gulbins, Erich and Carpinteiro, Alexander}, title = {Acid Sphingomyelinase Deficiency Ameliorates Farber Disease}, series = {International journal of molecular sciences}, volume = {20}, journal = {International journal of molecular sciences}, number = {24}, publisher = {MDPI}, address = {Basel}, issn = {1422-0067}, doi = {10.3390/ijms20246253}, pages = {18}, year = {2019}, abstract = {Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can't achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.}, language = {en} } @article{HoehnJerniganJaptoketal.2017, author = {Hoehn, Richard S. and Jernigan, Peter L. and Japtok, Lukasz and Chang, Alex L. and Midura, Emily F. and Caldwell, Charles C. and Kleuser, Burkhard and Lentsch, Alex B. and Edwards, Michael J. and Gulbins, Erich and Pritts, Timothy A.}, title = {Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation}, series = {Annals of surgery : a monthly review of surgical science and practice}, volume = {265}, journal = {Annals of surgery : a monthly review of surgical science and practice}, number = {1}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0003-4932}, doi = {10.1097/SLA.0000000000001648}, pages = {218 -- 226}, year = {2017}, abstract = {Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.}, language = {en} } @article{McVeyKimTabuchietal.2017, author = {McVey, Mark J. and Kim, Michael and Tabuchi, Arata and Srbely, Victoria and Japtok, Lukasz and Arenz, Christoph and Rotstein, Ori and Kleuser, Burkhard and Semple, John W. and Kuebler, Wolfgang M.}, title = {Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets}, series = {American journal of physiology : Lung cellular and molecular physiology}, volume = {312}, journal = {American journal of physiology : Lung cellular and molecular physiology}, number = {5}, publisher = {American Physiological Society}, address = {Bethesda}, issn = {1040-0605}, doi = {10.1152/ajplung.00317.2016}, pages = {625 -- 637}, year = {2017}, abstract = {Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.}, language = {en} } @article{ReichelRheinHofmannetal.2018, author = {Reichel, Martin and Rhein, Cosima and Hofmann, Lena M. and Monti, Juliana and Japtok, Lukasz and Langgartner, Dominik and F{\"u}chsl, Andrea M. and Kleuser, Burkhard and Gulbins, Erich and Hellerbrand, Claus and Reber, Stefan O. and Kornhuber, Johannes}, title = {Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation}, series = {Frontiers in Psychiatry}, volume = {9}, journal = {Frontiers in Psychiatry}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-0640}, doi = {10.3389/fpsyt.2018.00496}, pages = {8}, year = {2018}, abstract = {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.}, language = {en} } @article{MeinersPalmieriKlopfleischetal.2019, author = {Meiners, Jana and Palmieri, Vittoria and Klopfleisch, Robert and Ebel, Jana-Fabienne and Japtok, Lukasz and Schumacher, Fabian and Yusuf, Ayan Mohamud and Becker, Katrin Anne and Z{\"o}ller, Julia and Hose, Matthias and Kleuser, Burkhard and Hermann, Dirk Matthias and Kolesnick, Richard N. and Buer, Jan and Hansen, Wiebke and Westendorf, Astrid M.}, title = {Intestinal acid sphingomyelinase protects from severe Pathogen-Driven Colitis}, series = {Frontiers in immunology}, volume = {10}, journal = {Frontiers in immunology}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-3224}, doi = {10.3389/fimmu.2019.01386}, pages = {14}, year = {2019}, abstract = {Inflammatory diseases of the gastrointestinal tract are emerging as a global problem with increased evidence and prevalence in numerous countries. A dysregulated sphingolipid metabolism occurs in patients with ulcerative colitis and is discussed to contribute to its pathogenesis. In the present study, we determined the impact of acid sphingomyelinase (Asm), which catalyzes the hydrolysis of sphingomyelin to ceramide, on the course of Citrobacter (C.) rodentium-driven colitis. C. rodentium is an enteric pathogen and induces colonic inflammation very similar to the pathology in patients with ulcerative colitis. We found that mice with Asm deficiency or Asm inhibition were strongly susceptible to C. rodentium infection. These mice showed increased levels of C. rodentium in the feces and were prone to bacterial spreading to the systemic organs. In addition, mice lacking Asm activity showed an uncontrolled inflammatory T(h)1 and T(h)17 response, which was accompanied by a stronger colonic pathology compared to infected wild type mice. These findings identified Asm as an essential regulator of mucosal immunity to the enteric pathogen C. rodentium.}, language = {en} } @article{CarpinteiroBeckerJaptoketal.2015, author = {Carpinteiro, Alexander and Becker, Katrin Anne and Japtok, Lukasz and Hessler, Gabriele and Keitsch, Simone and Pozgajova, Miroslava and Schmid, Kurt W. and Adams, Constantin and M{\"u}ller, Stefan and Kleuser, Burkhard and Edwards, Michael J. and Grassme, Heike and Helfrich, Iris and Gulbins, Erich}, title = {Regulation of hematogenous tumor metastasis by acid sphingomyelinase}, series = {EMBO molecular medicine}, volume = {7}, journal = {EMBO molecular medicine}, number = {6}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1757-4676}, pages = {714 -- 734}, year = {2015}, abstract = {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.}, language = {en} } @article{ZoicasSchumacherKleuseretal.2020, author = {Zoicas, Iulia and Schumacher, Fabian and Kleuser, Burkhard and Reichel, Martin and Gulbins, Erich and Fejtova, Anna and Kornhuber, Johannes and Rhein, Cosima}, title = {The forebrain-specific overexpression of acid sphingomyelinase induces depressive-like symptoms in mice}, series = {Cells}, volume = {9}, journal = {Cells}, number = {5}, publisher = {MDPI}, address = {Basel}, pages = {12}, year = {2020}, abstract = {Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.}, language = {en} }