Abstract
Emerging evidence suggests a complex relationship between sphingosine 1-phosphate (S1P) signaling and stroke. Here, we show the kinetics of S1P in the acute phase of ischemic stroke and highlight accompanying changes in immune cells and S1P receptors (S1PR). Using a C57BL/6 mouse model of middle cerebral artery occlusion (MCAO), we assessed S1P concentrations in the brain, plasma, and spleen. We found a steep S1P gradient from the spleen towards the brain. Results obtained by qPCR suggested that cells expressing the S1PR type 1 (S1P1+) were the predominant population deserting the spleen. Here, we report the cerebral recruitment of T helper (TH) and regulatory T (TREG) cells to the ipsilateral hemisphere, which was associated with differential regulation of cerebral S1PR expression patterns in the brain after MCAO. This study provides insight that the S1P-S1PR axis facilitates splenic T cell egress and is linked to the cerebral recruitment of S1PR+ TH and TREG cells. Further insights by which means the S1P-S1PR-axis orchestrates neuronal positioning may offer new therapeutic perspectives after ischemic stroke.
Highlights
In the last two decades, the formerly enigmatic sphingolipids and their metabolism have aroused a lot of biomedical research interest due to their pivotal role as signaling molecules
In order to study the potential of sphingosine 1-phosphate (S1P) to act as a chemotactic agent in cerebral ischemia, we established a temporal profile of S1P concentrations in the murine spleen, plasma, and brain in a model of acute cerebral ischemia (MCAO)
In humans, who had suffered from acute ischemic stroke (Str), we were able to measure similar changes 24 h after onset of ischemia as compared to healthy controls (C) (C vs. Str; 4.55 ± 2.1 ng/mg vs. 6.53 ± 5.0 ng/mg, p = 0.0034, Figure 1B)
Summary
In the last two decades, the formerly enigmatic sphingolipids and their metabolism have aroused a lot of biomedical research interest due to their pivotal role as signaling molecules. The successful application of fingolimod in the treatment of various diseases characterized by a perturbed S1P metabolism suggests the strong therapeutic potential of the S1P-S1PR-axis [8,10,11,12]. S1P is conceived to regulate immune cell recruitment towards high S1P gradients [13,14] by ligating the five bona fide S1PR type 1–5 (S1P1–5) [15]. This gradient is perturbed under diseased conditions and S1PR signaling acts as a driver of multiple diseases [16]. How the S1P-S1PR-axis contributes to pathology in focal cerebral ischemia has not been elucidated in all details [17,18,19]
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