A Sphingosine 1-Phosphate Gradient Is Linked to the Cerebral Recruitment of T Helper and Regulatory T Helper Cells during Acute Ischemic Stroke

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 (S1P_R). 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 S1P_R type 1 (S1P₁⁺) were the predominant population deserting the spleen. Here, we report the cerebral recruitment of T helper (T_H) and regulatory T (T_REG) cells to the ipsilateral hemisphere, which was associated with differential regulation of cerebral S1P_R expression patterns in the brain after MCAO. This study provides insight that the S1P-S1P_R axis facilitates splenic T cell egress and is linked to the cerebral recruitment of S1P_R⁺ T_H and T_REG cells. Further insights by which means the S1P-S1P_R-axis orchestrates neuronal positioning may offer new therapeutic perspectives after ischemic stroke.

Keywords: ceramides; fingolimod; regulatory T helper cells; sphingosine 1-phosphate; sphingosine 1-phosphate receptor; sphingosine kinase; stroke.