Abstract
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.
Highlights
Granulocyte colony-stimulating factor (G-CSF) induces migration of neutrophils by upregulation of the chemokine receptor CXCR2
Because granulocyte-colony stimulating factor (G-CSF) induces CXCR2 expression, we suggested that CerS2 is required for proper activation of the G-CSF-R and thereby promotes the expression of CXCR2 and the neutrophil migration potential
Our data revealed that the presence of very long chain ceramides is essential for G-CSF signaling
Summary
Granulocyte colony-stimulating factor (G-CSF) induces migration of neutrophils by upregulation of the chemokine receptor CXCR2. These kinases phosphorylate one or more tyrosine residues in the C-terminal region of the G-CSF-R leading to the activation of multiple intracellular signaling proteins, including the signal transducers and activators of transcription (STAT) and mitogen-activated protein (MAP) kinases[5,6,7] This signaling pathway is regulated by suppressor of cytokine signaling 3 (SOCS3) which is induced by STAT3 and inhibits the catalytic activity of Jak and thereby, the expression of STAT3. We demonstrated that expression of CXCR2 in neutrophils induced by G-CSF is regulated by ceramide synthases (CerS2 and CerS6). We investigate the hypothesis that a deficiency in ceramides with specific acyl chain lengths alters membrane properties and thereby prevents or promotes G-CSF signaling
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