The synthesis and metabolism of fat molecules known as ceramides is linked to G-CSF signaling, which increases white blood cell infiltration into the central nervous system and results in inflammation in patients with multiple sclerosis (MS), a new study shows.
The study titled, “The relevance of ceramides and their synthesizing enzymes for multiple sclerosis,” was published in the journal Clinical Science.
One of the main disease characteristics of MS is that immune white blood cells — such as T-cells, B-cells, monocytes and neutrophils — infiltrate the central nervous system. Once there, these cells secrete molecules that promote an inflammatory process.
Recently, studies have shown that lipid (fat) molecules known as ceramides play a role in the development of MS. Ceramides are synthesized by enzymes known as ceramide synthases (CerS), like CerS2.
Ceramides also can be chemically modified by the addition of other groups. These molecules can be glucosylceramides, which are ceramides attached to a sugar molecule, or lactosylceramide, which is a type of ceramide that incorporates lactose.
An enzyme known as UDP-glucose ceramide glucosyltransferase (UGCG) synthesizes glucosylceramides.
Interestingly, research has shown that a genetic deletion of CerS2 improves the pathology of experimental autoimmune encephalomyelitis (EAE) — a demyelinating disease that is similar to MS. Such improvement is linked to reduced expression of CXCR2, a molecule that is present on the surface of neutrophils and plays a role in migration into the central nervous system.
Furthermore, researchers have demonstrated that CXCR2 expression in neutrophils is induced by a molecule called G-CSF (granulocyte-colony stimulating factor) that is regulated in a CerS2-dependent manner.
However, it is still unclear if ceramides and their interaction with CXCR2 play a role in MS.
Therefore, researchers now have analyzed the gene expression of G-CSFR (the receptor that G-CSF binds to and signals through), CXCR2, CerS2, CerS6, and UGCG in white blood cells from MS patients. The results were compared to those of healthy people used as study controls.
Researchers also investigated the number of immune cells and levels of different ceramide, glycosylceramide (GluCer) and lactosylceramide (LacCer) molecules in plasma and white blood cells from MS patients and healthy subjects.
The team recruited 72 MS patients and 25 healthy volunteers. Blood samples were collected from healthy controls over a one-year period, and from MS patients over a three-year period.
First, researchers found that the ceramide molecules C16-LacCer and C24-Cer were downregulated in white blood cells of MS patients compared to healthy controls.
When analyzing the numbers of white blood cells, researchers found that in MS patients there was an increased number of B-cells, while there were no changes in the population of T-cells or neutrophils.
Next researchers investigated whether ceramide synthesizing and metabolizing enzymes such as CerS2, CerS6 and UGCG also were altered in white blood cells isolated from MS patients.
Gene expression of ceramide-metabolizing enzymes and G-CSF-signaling enzymes were found to be significantly increased in MS patients. Interestingly, the activity of GCSFR and CXCR2 correlated with CerS2 and UGCG gene expression.
Hence, high levels of CerS2 and UGCG, both of which synthesize certain types of ceramides, are associated with increased GCSF/CXCR2 signaling, which, in turn, is associated with increased migration of neutrophils into the central nervous system.
“These data indicate that in MS patients there is a potential link between G-CSF signaling and ceramide metabolism,” the researchers wrote.
The team also believes that “ceramides have potential as biomarkers for MS,” they wrote.
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