The relevance of ceramides and their synthesizing enzymes for multiple sclerosis

Abstract

Ceramide synthases (CerS) synthesize chain length specific ceramides (Cer), which mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that the genetic deletion of CerS2 suppresses EAE pathology by interaction with granulocyte-colony stimulating factor (G-CSF) signaling and CXC motif chemokine receptor 2 (CXCR2) expression, leading to impaired neutrophil migration. In the present study, we investigated the importance of Cers and their synthesizing/metabolizing enzymes in MS. For this purpose, a longitudinal study with 72 MS patients and 25 healthy volunteers was performed. Blood samples were collected from healthy controls and MS patients over 1- or 3-year periods, respectively. Immune cells were counted using flow cytometry, ceramide levels were determined using liquid chromatography-tandem mass spectrometry, and mRNA expression was analyzed using quantitative PCR. In white blood cells, C16-LacCer and C24-Cer were down-regulated in MS patients in comparison with healthy controls. In plasma, C16-Cer, C24:1-Cer, C16-GluCer, and C24:1-GluCer were up-regulated and C16-LacCer was down-regulated in MS patients in comparison with healthy controls. Blood samples from MS patients were characterized by an increased B-cell number. However, there was no correlation between B-cell number and Cer levels. mRNA expression of Cer metabolizing enzymes and G-CSF signaling enzymes was significantly increased in MS patients. Interestingly, G-CSF receptor (G-CSFR) and CXCR2 mRNA expression correlated with CerS2 and UDP-glucose Cer glucosyltransferase (UGCG) mRNA expression. In conclusion, our results indicate that Cer metabolism is linked to G-CSF signaling in MS.

Gut Microbiome and Metabolome Were Altered and Strongly Associated With Platelet Count in Adult Patients With Primary Immune Thrombocytopenia

“…In addition, PICRUSt analysis revealed that the enriched KEGG pathways of gut microbiota in ITP mostly focused on lipid metabolism. Previous studies demonstrated important role of abnormal lipid metabolism in autoimmune diseases, such as diabetes and multiple sclerosis ( Kim, 2017 ; Kurz et al, 2018 ). Therefore, we proposed possible involvement of lipids and lipid-like molecules in the onset and development of ITP.…”

Advances in determining signaling mechanisms of ceramide and role in disease

“…Elevated levels of ceramides have been observed in individuals with multiple sclerosis and in blood cells of experimental autoimmune encephalomyelitis mice, a model for multiple sclerosis (49). Through KO of CerS2 and CerS6 in experimental autoimmune encephalomyelitis mice, it has been proposed that the ratio of C16/C24-ceramide at the plasma membrane of neutrophils may regulate membrane properties and, thereby, the function of receptors and proteins important for cell migration.…”

Analysis of urinary sphingolipids using liquid chromatography‐tandem mass spectrometry in diabetic nephropathy

“…Reportedly, ceramides and other sphingolipids possess important roles in various pathophysiological conditions, including stress responses, apoptosis, inflammation and proliferation [4][5][6][7][8] . Therefore, they are thought to be involved in the pathogenesis of various diseases, including diabetes mellitus [9][10][11] , neurodegenerative disorders 12 , multiple sclerosis 13 and coronary artery disease 14 .…”