Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
Neurochem Int. 2021 Jun;146:105018. doi: 10.1016/j.neuint.2021.105018. Epub 2021 Mar 13.
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid which modulates vascular integrity through its receptors, S1P-S1P. Notably, S1P has been shown to mediate the disruption of cerebrovascular integrity in vitro and in vivo. However, the mechanism underlying this process has not been fully elucidated. We evaluated the role of S1P in blood-brain barrier (BBB) disruption induced by lipopolysaccharide (LPS)-mediated systemic inflammation and found that BBB disruption and neutrophil infiltration were significantly attenuated in S1pr2 mice relative to S1pr2 littermates. This is concomitant with attenuation of LPS-induced transcriptional activation of IL-6 and downregulation of occludin. Furthermore, S1pr2 mice had significantly reduced expression of genes essential for neutrophil infiltration: Sele, Cxcl1, and Cxcl2. Conversely, pharmacological agonism of S1P induced transcriptional activation of E-selectin in vitro and in vivo. Although S1P does not appear to be required for activation of microglia, stimulation of microglial cells with the S1P potentiated the response of endothelial cells to LPS. These results demonstrate that S1P promotes LPS-induced neutrophil extravasation by inducing expression of endothelial adhesion molecule gene, Sele, and potentiating microglial inflammation of endothelial cells. It is likely that S1P is a mediator of cerebrovascular inflammation and represents a potential therapeutic target for neurodegenerative disease such as vascular cognitive impairment.
鞘氨醇 1-磷酸（S1P）是一种生物活性鞘脂，通过其受体 S1P-S1P 调节血管完整性。值得注意的是，S1P 已被证明在体外和体内介导脑血管完整性的破坏。然而，这一过程的机制尚未完全阐明。我们评估了 S1P 在脂多糖（LPS）介导的全身炎症引起的血脑屏障（BBB）破坏中的作用，发现与 S1pr2 同窝仔相比，S1pr2 小鼠的 BBB 破坏和中性粒细胞浸润明显减轻。这与 LPS 诱导的 IL-6 转录激活和封闭蛋白下调一致。此外，S1pr2 小鼠的中性粒细胞浸润所必需的基因表达明显降低：Sele、Cxcl1 和 Cxcl2。相反，S1P 的药理学激动剂在体外和体内诱导了 E-选择素的转录激活。虽然 S1P 似乎不是激活小胶质细胞所必需的，但 S1P 刺激小胶质细胞可增强内皮细胞对 LPS 的反应。这些结果表明，S1P 通过诱导内皮细胞黏附分子基因 Sele 的表达和增强小胶质细胞对内皮细胞的炎症反应，促进 LPS 诱导的中性粒细胞渗出。S1P 可能是脑血管炎症的介质，代表了血管性认知障碍等神经退行性疾病的潜在治疗靶点。
