Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis

J Immunol. 2012 Jun 1;188(11):5723-33. doi: 10.4049/jimmunol.1103109. Epub 2012 Apr 27.


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.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / enzymology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Humans
  • Inflammation / enzymology
  • Inflammation / immunology
  • Inflammation / pathology
  • Interferon-gamma / physiology
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / cerebrospinal fluid
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Nitric Oxide / metabolism
  • Sphingosine N-Acyltransferase / biosynthesis
  • Sphingosine N-Acyltransferase / cerebrospinal fluid
  • Sphingosine N-Acyltransferase / physiology*
  • Young Adult


  • Membrane Proteins
  • Nitric Oxide
  • Interferon-gamma
  • CERS6 protein, human
  • Sphingosine N-Acyltransferase