title: Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis.
abstract: Ceramides are mediators of apoptosis and inflammatory processes. In an animal model of multiple sclerosis (MS), the experimental autoimmune encephalomyelitis (EAE) model, we observed a significant elevation of C(16:0)-Cer in the lumbar spinal cord of EAE mice. This was caused by a transiently increased expression of ceramide synthase (CerS) 6 in monocytes/macrophages and astroglia. Notably, this corresponds to the clinical finding that C(16:0)-Cer levels were increased 1.9-fold in cerebrospinal fluid of MS patients. NO and TNF-α secreted by IFN-γ-activated macrophages play an essential role in the development of MS. In murine peritoneal and mouse-derived RAW 264.7 macrophages, IFN-γ-mediated expression of inducible NO synthase (iNOS)/TNF-α and NO/TNF-α release depends on upregulation of CerS6/C(16:0)-Cer. Downregulation of CerS6 by RNA interference or endogenous upregulation of C(16:0)-Cer mediated by palmitic acid in RAW 264.7 macrophages led to a significant reduction or increase in NO/TNF-α release, respectively. EAE/IFN-γ knockout mice showed a significant delay in disease onset accompanied by a significantly less pronounced increase in CerS6/C(16:0)-Cer, iNOS, and TNF-α compared with EAE/wild-type mice. Treatment of EAE mice with l-cycloserine prevented the increase in C(16:0)-Cer and iNOS/TNF-α expression and caused a remission of the disease. In conclusion, CerS6 plays a critical role in the onset of MS, most likely by regulating NO and TNF-α synthesis. CerS6 may represent a new target for the inhibition of inflammatory processes promoting MS development.
authors.affiliation: Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt/Main, Germany. susanne.schiffmann@med.uni-frankfurt.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Schiffmann
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.forename: Kerstin
authors.initials: K
authors.lastname: Birod
authors.forename: Max
authors.initials: M
authors.lastname: Eberle
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schreiber
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pfeilschifter
authors.forename: Ulf
authors.initials: U
authors.lastname: Ziemann
authors.forename: Sandra
authors.initials: S
authors.lastname: Pierre
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000134:cerebrospinal fluid / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000096:biosynthesis / Q000134:cerebrospinal fluid / Q000502:physiology*; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase