Role of ceramide synthase 2 in G-CSF signaling and G-CSF-R translocation into detergent-resistant membranes

Sci Rep. 2019 Jan 24;9(1):747. doi: 10.1038/s41598-018-37342-8.


Ceramides are sphingolipids with defined acyl chain lengths, which are produced by corresponding ceramide synthases (CerS1-6). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), the ablation of CerS2 suppresses EAE-pathology by reducing neutrophil migration into the central nervous system. This migration is induced by granulocyte-colony stimulating factor (G-CSF) signaling. G-CSF signaling leads to a signal cascade including the phosphorylation of Lyn kinase and STAT3. This in turn regulates expression of the neutrophil surface receptor chemokine receptor 2 (CXCR2) and causes translocation of the receptor into detergent-resistant membranes (DRMs). In this study we investigated the role of ceramides in G-CSF signaling. We found, that G-CSF treatment of wild type bone marrow cells (BMCs) leads to translocation of G-CSF-receptor (G-CSF-R) into DRMs. G-CSF also induces downregulation of ceramides in WT and CerS2 null BMCs, as well as upregulation of very long chain lactosylceramides. However, in CerS2 null BMCs, G-CSF failed to induce translocation of G-CSF-R into DRMs, leading to reduced phosphorylation of Lyn and reduced CXCR2 expression. Interestingly, G-CSF signaling in CerS6 null BMCs was not affected. In conclusion, very long chain ceramides are important for G-CSF signaling and translocation of G-CSF-R into DRMs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / genetics
  • Cell Movement / drug effects
  • Detergents / pharmacology
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Regulation / drug effects
  • Granulocyte Colony-Stimulating Factor / genetics*
  • Humans
  • Lactosylceramides / metabolism
  • Mice
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Neutrophils / drug effects
  • Protein Transport / drug effects
  • Receptors, Granulocyte Colony-Stimulating Factor / genetics*
  • STAT3 Transcription Factor / genetics
  • Sphingosine N-Acyltransferase / genetics*
  • src-Family Kinases / genetics


  • Detergents
  • Lactosylceramides
  • Receptors, Granulocyte Colony-Stimulating Factor
  • STAT3 Transcription Factor
  • Granulocyte Colony-Stimulating Factor
  • CERS6 protein, mouse
  • Cers2 protein, mouse
  • Sphingosine N-Acyltransferase
  • lyn protein-tyrosine kinase
  • src-Family Kinases