Dataset Information

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

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.

SUBMITTER: Lucaciu A

PROVIDER: S-EPMC7503682 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Lucaciu Alexandra A Kuhn Hannah H Trautmann Sandra S Ferreirós Nerea N Steinmetz Helmuth H Pfeilschifter Josef J Brunkhorst Robert R Pfeilschifter Waltraud W Subburayalu Julien J Vutukuri Rajkumar R

International journal of molecular sciences 20200828 17

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<sub>R</sub>). 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 sug ...[more]

PMID: 32872326

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Project description:Background: The contribution of metabolic profile to the cerebral collateral circulation in acute ischemic stroke (AIS) has not been fully outlined. In this study, we conducted a metabolomic study to assess the relationship between the metabolic biomarkers and the collateral status of AIS. Methods: A two-stage study was conducted from September 2019 to June 2021 in our hospital. There were 96 subjects including 66 patients with AIS and 30 healthy controls in the discovery stage and 80 subjects including 53 patients with AIS and 27 healthy controls in the validation stage. Collateral circulation was assessed by the Tan score based on computed tomographic angiography (CTA). Liquid chromatography-tandem mass spectrometry was used to identify differential metabolic markers. Then, an ELISA was employed to detect the plasma levels of sphingosine-1-phosphate (S1P). Results:There were 114 differential metabolites between patients with AIS and control groups and 37 differential metabolites between good collateral circulation (GCC) and poor collateral circulation (PCC) groups. The pathway enrichment analysis revealed that arginine biosynthesis was the only statistically significant pathway between AIS and control groups and sphingolipid metabolism was the only statistically significant pathway between GCC and PCC groups. The differential metabolites sphinganine-1-phosphate (SA1P) and S1P belong to the sphingolipid metabolism. In the discovery stage, when the GCC group was compared with the PCC group, the receiver operating characteristic (ROC) analysis showed that plasma SA1P relative levels demonstrated an area under the curve (AUC) of 0.719 (95% CI: 0.582-0.834), and S1P levels demonstrated an AUC of 0.701 (95% CI: 0.567-0.819). In addition, both plasma SA1P and S1P relative levels showed significant negative correlations with the 90-day modified Rankin Scale (mRS) score. In the validation sample, higher plasma S1P levels were independent predictors of GCC (p = 0.014), and plasma S1P levels demonstrated an AUC of 0.738 (95% CI: 0.599-0.849) to differentiate patients with GCC from patients with PCC. In addition, plasma S1P levels also showed significant negative correlations with the 90-day mRS score. Conclusion: We first illustrated the association between plasma metabolic profiles and cerebral collateral circulation in patients with AIS. Plasma S1P levels might be a potential diagnostic biomarker for predicting collateral circulation status in patients with AIS.

Project description:Rationale: Emerging evidence has suggested that sphingosine 1-phosphate (S1P), a bioactive metabolite of sphingolipids, may play an important role in the pathophysiological processes of cerebral hypoxia and ischemia. However, the influence of S1P on cerebral hemodynamics and metabolism remains unclear. Material and Methods: Uniquely capable of high-resolution, label-free, and comprehensive imaging of hemodynamics and oxygen metabolism in the mouse brain without the influence of general anesthesia, our newly developed head-restrained multi-parametric photoacoustic microscopy (PAM) is well suited for this mechanistic study. Here, combining the cutting-edge PAM and a selective inhibitor of sphingosine kinase 2 (SphK2) that can increase the blood S1P level, we investigated the role of S1P in cerebral oxygen supply-demand and its neuroprotective effects on global brain hypoxia induced by nitrogen gas inhalation and focal brain ischemia induced by transient middle cerebral artery occlusion (tMCAO). Results: Inhibition of SphK2, which increased the blood S1P, resulted in the elevation of both arterial and venous sO2 in the hypoxic mouse brain, while the cerebral blood flow remained unchanged. As a result, it gradually and significantly reduced the metabolic rate of oxygen. Furthermore, pre-treatment of the mice subject to tMCAO with the SphK2 inhibitor led to decreased infarct volume, improved motor function, and reduced neurological deficit, compared to the control treatment with a less potent R-enantiomer. In contrast, post-treatment with the inhibitor showed no improvement in the stroke outcomes. The failure for the post-treatment to induce neuroprotection was likely due to the relatively slow hemodynamic responses to the SphK2 inhibitor-evoked S1P intervention, which did not take effect before the brain injury was induced. Conclusions: Our results reveal that elevated blood S1P significantly changes cerebral hemodynamics and oxygen metabolism under hypoxia but not normoxia. The improved blood oxygenation and reduced oxygen demand in the hypoxic brain may underlie the neuroprotective effect of S1P against ischemic stroke.

Project description:Ischemic strokes account for about 80% of all strokes and are associated with a high risk of mortality. Angiogenesis of brain microvascular endothelial cells may contribute to functional restoration following ischemia. Fibroblast growth factor 1 (FGF1), a member of FGF superfamily, involved in embryonic development, angiogenesis, wound healing, and neuron survival. However, the mitogenic activity of FGF1 is known to contribute to several human pathologies, thereby questioning the safety of its clinical applications. Here, we explored the effects and mechanism of action of non-mitogenic FGF1 (nmFGF1) on angiogenesis in mice after ischemia stroke and an oxygen-glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) injury model. We found that intranasal administration nmFGF1 significantly promoted angiogenesis in mice after stroke, and significantly increased the formation of matrigel tube and promoted scratch migration in a dose-dependent manner in OGD-induced HBMECs in vitro. However, the co-administration of an FGF receptor 1 (FGFR1)-specific inhibitor PD173074 significantly reversed the effects of nmFGF1 in vitro, suggesting that nmFGF1 functions via FGFR1 activation. Moreover, nmFGF1 activated sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) in mice after stroke in vivo. S1P1 protein antagonist VPC23019 and agonist FTY720 were used to confirm that nmFGF1 promotes angiogenesis in vitro partially through the S1P1 pathway. OGD induced downregulation of S1P1 expression. The S1P1 antagonist VPC23019 blocked the stimulatory effects of nmFGF1, whereas the S1P1 agonist FTY720 exerted effects comparable with those of nmFGF1. Furthermore, PD173074 reversed the effect of nmFGF1 on upregulating S1P1 signaling. In conclusion, nmFGF1 enhanced angiogenesis in mice following stroke and OGD-induced HBMECs through S1P1 pathway regulation mediated via FGFR1 activation. This new discovery suggests the potential therapeutic role of nmFGF1 for the treatment of ischemic strokes.

Dataset Information

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

Publications

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

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