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Abstract
BackgroundTick-borne encephalitis (TBE) is a serious acute central nervous system infection that can result in death or long-term neurological dysfunctions. We hypothesize that changes in sphingosine-1-phosphate (S1P) concentration occur during TBE development.MethodsS1P and interleukin-6 (IL-6) concentrations in blood plasma and cerebrospinal fluid (CSF) were measured using HPLC and ELISA, respectively. The effects of S1P on cytoskeletal structure and IL-6 production were assessed using rat astrocyte primary cultures with and without addition of plasma gelsolin and the S1P receptor antagonist fingolimod phosphate (FTY720P).ResultsWe report that acute inflammation due to TBE virus infection is associated with elevated levels of S1P and IL-6 in the CSF of infected patients. This elevated concentration is observed even at the earliest neurologic stage of disease, and may be controlled by glucocorticosteroid anti-inflammatory treatment, administered to patients unresponsive to antipyretic drugs and who suffer from a fever above 39°C. In vitro, treatment of confluent rat astrocyte monolayers with a high concentration of S1P (5 μM) results in cytoskeletal actin remodeling that can be prevented by the addition of recombinant plasma gelsolin, FTY720P, or their combination. Additionally, gelsolin and FTY720P significantly decreased S1P-induced release of IL-6.ConclusionsTBE is associated with increased concentration of S1P and IL-6 in CSF, and this increase might promote development of inflammation. The consequences of increased extracellular S1P can be modulated by gelsolin and FTY720P. Therefore, blocking the inflammatory response at sites of infection by agents modulating S1P pathways might aid in developing new strategies for TBE treatment.
Highlights
Tick-borne encephalitis (TBE) is a serious acute central nervous system infection that can result in death or long-term neurological dysfunctions
Comparing S1P concentration at different stages of TBE, as shown in Figure 2, we found that a short course of glucocorticosteroid treatment resulted in a significant decrease of S1P concentration in the blood (P
In the CSF of TBE subjects not treated with glucocorticosteroids, S1P concentration continued to increase during the course of the disease and was significantly higher (P
Summary
Tick-borne encephalitis (TBE) is a serious acute central nervous system infection that can result in death or long-term neurological dysfunctions. We have shown that plasma gelsolin, an actin-binding PIP2-regulated protein, can act as a universal carrier or scavenger of S1P, and its function may include interference with S1P actions [14]. Such an interaction may be of importance in settings where the concentrations of both substances change over their homeostatic ranges. An inflammatory reaction accompanied by central nervous system (CNS) infections such as tick-borne encephalitis (TBE) or Lyme neuroborreliosis (LNB), results in blood and cerebrospinal fluid (CSF) alterations in plasma gelsolin [15]. FTY720P, a S1P receptor modulator, was found to be highly effective in the treatment of MS [19], and its immunomodulatory activity may be potentially beneficial in other CNS inflammatory conditions
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