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 - GEN A1 - Plöhn, Svenja A1 - Edelmann, Bärbel A1 - Japtok, Lukasz A1 - He, Xingxuan A1 - Hose, Matthias A1 - Hansen, Wiebke A1 - Schuchman, Edward H. A1 - Eckstein, Anja A1 - Berchner-Pfannschmidt, Utta T1 - CD40 enhances sphingolipids in orbital fibroblasts BT - potential role of sphingosine-1-phosphate in inflammatory T-cell migration in Graves' orbitopathy T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - PURPOSE. Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1099 KW - Grave’s orbitopathy KW - sphingosine-1-phosphate KW - sphingolipids KW - inflammation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-468837 SN - 1866-8372 IS - 1099 ER - TY - JOUR A1 - Plöhn, Svenja A1 - Edelmann, Bärbel A1 - Japtok, Lukasz A1 - He, Xingxuan A1 - Hose, Matthias A1 - Hansen, Wiebke A1 - Schuchman, Edward H. A1 - Eckstein, Anja A1 - Berchner-Pfannschmidt, Utta T1 - CD40 enhances sphingolipids in orbital fibroblasts BT - potential role of sphingosine-1-phosphate in inflammatory T-Cell migration in graves' orbitopathy JF - Investigative ophthalmology & visual science N2 - METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management. KW - inflammation Y1 - 2018 U6 - https://doi.org/10.1167/iovs.18-25466 SN - 0146-0404 SN - 1552-5783 VL - 59 IS - 13 SP - 5391 EP - 5397 PB - Association for Research in Vision and Opthalmology CY - Rockville ER -