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; Kühn, Harald; Trautmann, Sandra; Ferreiròs, Nerea; Steinmetz, Helmuth; Pfeilschifter, Josef; Brunkhorst, R.; Pfeilschifter, Waltraud; Subburayalu, Julien; Vutukuri, Rajkumar

doi:10.3390/ijms21176242

Cited by 23 publications

(32 citation statements)

References 77 publications

(106 reference statements)

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“…In line with previous results, fingolimod reduced CD3+ cell infiltration in the brains of young mice [17,18]. Recent research suggests this might be primordially due to interference with S1P receptor signalling which facilitates recruitment of splenic T cells to the infarcted hemisphere [80]. FoxP3+ cells, meanwhile, represented approximately 10% of all infiltrating T cells in saline-treated young mice, in broad agreement with other studies [19].…”

Section: Discussionsupporting

confidence: 91%

The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia

Malone

Díaz

Shearer

et al. 2021

J Neuroinflammation

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Background The role of the immune system in stroke is well-recognised. Fingolimod, an immunomodulatory agent licensed for the management of relapsing-remitting multiple sclerosis, has been shown to provide benefit in rodent models of stroke. Its mechanism of action, however, remains unclear. We hypothesised fingolimod increases the number and/or function of regulatory T cells (Treg), a lymphocyte population which promotes stroke recovery. The primary aim of this study was to rigorously investigate the effect of fingolimod on Tregs in a mouse model of brain ischaemia. The effect of fingolimod in mice with common stroke-related comorbidities (ageing and hypercholesteremia) was also investigated. Methods Young (15–17 weeks), aged C57BL/6 mice (72–73 weeks), and ApoE−/− mice fed a high-fat diet (20–21 weeks) underwent permanent electrocoagulation of the left middle cerebral artery. Mice received either saline or fingolimod (0.5 mg/kg or 1 mg/kg) at 2, 24, and 48 h post-ischaemia via intraperitoneal injection. Another cohort of young mice (8–9, 17–19 weeks) received short-term (5 days) or long-term (10 days) fingolimod (0.5 mg/kg) treatment. Flow cytometry was used to quantify Tregs in blood, spleen, and lymph nodes. Immunohistochemistry was used to quantify FoxP3+ cell infiltration into the ischaemic brain. Results Fingolimod significantly increased the frequency of Tregs within the CD4+ T cell population in blood and spleen post-ischaemia in all three mouse cohorts compared to untreated ischemic mice. The highest splenic Treg frequency in fingolimod-treated mice was observed in ApoE−/− mice (9.32 ± 1.73% vs. 7.8 ± 3.01% in young, 6.09 ± 1.64% in aged mice). The highest circulating Treg frequency was also noted in ApoE−/− mice (8.39 ± 3.26% vs. 5.43 ± 2.74% in young, 4.56 ± 1.60% in aged mice). Fingolimod significantly increased the number of FoxP3+ cells in the infarct core of all mice. The most pronounced effects were seen when mice were treated for 10 days post-ischaemia. Conclusions Fingolimod increases Treg frequency in spleen and blood post-ischaemia and enhances the number of FoxP3+ cells in the ischaemic brain. The effect of fingolimod on this regulatory cell population may underlie its neuroprotective activity and could be exploited as part of future stroke therapy.

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Section: Discussionsupporting

confidence: 91%

The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia

Malone

Díaz

Shearer

et al. 2021

J Neuroinflammation

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“…As summarized above, the SphKs/S1P/S1PRs axis is involved in the regulation of many pathophysiological processes after cerebral ischemia. In this study, we found that patients with ischemic stroke had higher plasma S1P concentration compared with controls, similar to previous findings that circulating S1P levels were higher in patients with ischemic stroke than healthy controls (Testai et al, 2014 ; Lucaciu et al, 2020 ). Besides, we found that S1P had a significant negative correlation with the 90-day mRS score, indicating that higher S1P levels might predict favorable functional outcomes.…”

Section: Discussionsupporting

confidence: 92%

Association of Plasma Metabolic Biomarker Sphingosine-1-Phosphate With Cerebral Collateral Circulation in Acute Ischemic Stroke

Feng

et al. 2021

Front. Physiol.

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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.

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“…LECs also express intracellular adhesion molecule 1 (ICAM1) [39] as well as C-X3-C motif chemokine ligand 1 (CX3CL1) to guide DCs to lymphatic vessels in inflamed skin [40]. Further, LEC-derived sphingosine-1-phosphate (S1P) has been identified as a critical lipid mediator molecule that interacts with S1P receptor 1 (S1P1) on T cells to promote their egression from lymph nodes [41] and spleen [42].…”

Section: Lymphatics and The Immune Systemmentioning

confidence: 99%

Hepatic lymphatic vascular system in health and disease

Jeong

Tanaka

Iwakiri

2022

Journal of Hepatology

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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

Cited by 23 publications

References 77 publications

The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia

The effect of fingolimod on regulatory T cells in a mouse model of brain ischaemia

Association of Plasma Metabolic Biomarker Sphingosine-1-Phosphate With Cerebral Collateral Circulation in Acute Ischemic Stroke

Hepatic lymphatic vascular system in health and disease

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