School of Medical Sciences, UNSW Sydney, Kensington, NSW, Australia.
Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
J Neurochem. 2020 Apr;153(2):173-188. doi: 10.1111/jnc.14917. Epub 2019 Dec 6.
Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through a family of five G protein-coupled receptors, S1PR1-S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) is a potent S1P receptor agonist that causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties of FTY720 in several neurodegenerative paradigms; however, neuroprotective properties of the native ligand S1P have not been established. We aimed to establish the significance of neurotrophic factor up-regulation by S1P for neuroprotection, comparing S1P with FTY720. S1P induced brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), platelet-derived growth factor B (PDGFB), and heparin-binding EGF-like growth factor (HBEGF) gene expression in primary human and murine astrocytes, but not in neurons, and to a much greater extent than FTY720. Accordingly, S1P but not FTY720 protected cultured neurons against excitotoxic cell death in a primary murine neuron-glia coculture model, and a neutralizing antibody to LIF blocked this S1P-mediated neuroprotection. Antagonists of S1PR1 and S1PR2 both inhibited S1P-mediated neurotrophic gene induction in human astrocytes, indicating that simultaneous activation of both receptors is required. S1PR2 signaling was transduced through Gα and the small GTPase Rho, and was necessary for the up-regulation and activation of the transcription factors FOS and JUN, which regulate LIF, BDNF, and HBEGF transcription. In summary, we show that S1P protects hippocampal neurons against excitotoxic cell death through up-regulation of neurotrophic gene expression, particularly LIF, in astrocytes. This up-regulation requires both S1PR1 and S1PR2 signaling. FTY720 does not activate S1PR2, explaining its relative inefficacy compared to S1P.
鞘氨醇 1-磷酸（S1P）是一种重要的脂质代谢物，通过一个由五个 G 蛋白偶联受体（S1PR1-S1PR5）组成的家族传递信号，从而调节细胞生理学。多发性硬化症药物 fingolimod（FTY720）是一种有效的 S1P 受体激动剂，可导致外周淋巴细胞减少。最近的研究表明，FTY720 在几种神经退行性模型中具有直接的神经保护作用；然而，S1P 的天然配体的神经保护作用尚未确定。我们旨在确定 S1P 上调神经营养因子对神经保护的意义，将 S1P 与 FTY720 进行比较。S1P 诱导原代人和鼠星形胶质细胞中的脑源性神经营养因子（BDNF）、白血病抑制因子（LIF）、血小板衍生生长因子 B（PDGFB）和肝素结合表皮生长因子样生长因子（HBEGF）基因表达，但不诱导神经元表达，而且程度远大于 FTY720。因此，S1P 而不是 FTY720 可在原代鼠神经元-神经胶质共培养模型中保护培养的神经元免受兴奋性细胞死亡，而针对 LIF 的中和抗体可阻断这种 S1P 介导的神经保护作用。S1PR1 和 S1PR2 的拮抗剂均抑制 S1P 在人星形胶质细胞中的神经营养基因诱导，表明同时激活这两种受体是必需的。S1PR2 信号通过 Gα 和小 GTPase Rho 转导，对于调节 LIF、BDNF 和 HBEGF 转录的转录因子 FOS 和 JUN 的上调和激活是必需的。总之，我们表明 S1P 通过上调星形胶质细胞中神经营养基因表达，特别是 LIF，来保护海马神经元免受兴奋性细胞死亡。这种上调需要 S1PR1 和 S1PR2 信号。FTY720 不会激活 S1PR2，这解释了它与 S1P 相比相对无效的原因。
