Alterations in sphingolipid metabolism are described to contribute to
various neurological disorders. We here determined the expression of
enzymes involved in the sphingomyelin cycle and their products in
postmortem brain tissue of multiple sclerosis
(MS) patients. In parallel, we investigated the effect of the
sphingosine-1 receptor agonist Fingolimod (Gilenya(®)) on sphingomyelin
metabolism in reactive astrocytes and determined its functional
consequences for the process of neuro-inflammation. Our results
demonstrate that in active MS lesions, marked by large number of
infiltrated immune cells, an altered expression of enzymes involved in
the sphingomyelin cycle favors enhanced ceramide production. We
identified reactive astrocytes as the primary cellular source of
enhanced ceramide production in MS brain samples. Astrocytes isolated
from MS lesions expressed enhanced mRNA levels of the ceramide-producing
enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from
control white matter. In addition, TNF-α treatment induced ASM mRNA and
ceramide levels in astrocytes isolated from control white matter.
Incubation of astrocytes with Fingolimod prior to TNF-α treatment
reduced ceramide production and mRNA expression of ASM to control levels
in astrocytes. Importantly, supernatants derived from reactive
astrocytes treated with Fingolimod significantly reduced
transendothelial monocyte migration. Overall, the present study
demonstrates that reactive astrocytes represent a possible additional
cellular target for Fingolimod in MS by directly reducing the production
of pro-inflammatory lipids and limiting subsequent transendothelial
leukocyte migration.
The blood brain barrier keeps stuff out of the brain to maintianin its health, it consists of speciallised blood vessel cells that bind together tightly to make them inpenetrable. This is facilitated by factors produced by astrocytes that contact the blood vessel. This group finds that Gilenya may act on astrocytes to increase the production of a molecule that helps make the blood brain barrier less leaky to monocytes, which are macrophages in the blood. This suggests that Gilenya may not only stop (lymphocytes) white blood cells from entering the blood during MS but may also interfer with white blood cell (monocyte) entry into the brain also so a double whammy of benefit.