Control of sphingosine-1-phosphate distribution.

鞘氨醇-1-磷酸（S1P）信号脂质在哺乳动物生物学中起着重要作用。血液中S1P浓度高，血浆中S1P稳定血管内皮细胞之间的连接。与血液和淋巴相比，淋巴组织中S1P的浓度较低，需要S1P区隔化来维持适当的淋巴细胞循环。尽管淋巴器官中的S1P在稳态状态下较低，但S1P的浓度可能在炎症时增加，并且组织中S1P的增加已被报道促进血管生成并增强先天和适应性免疫细胞的促炎反应。靶向S1P信号和S1P代谢的药物作为免疫抑制剂目前正在临床试验中。通过阻断淋巴细胞离开淋巴样器官，这些药物阻止活化的T细胞到达移植器官或遭受自身免疫攻击的器官。这些药物也可能有直接的抗炎作用。尽管S1P具有重要的功能，但人们对其分布是如何控制的却知之甚少。为了维持较低的组织S1P，必须包含两个来源。首先，组织经常被血浆浸泡，以吸收营养并清除废物。血浆中的S1P必须被阻止进入或从器官中移除。其次，所有细胞都被认为在鞘脂膜代谢过程中产生胞内S1P。这种细胞内的S1P在分泌到间隙之前必须被破坏。本研究旨在探讨淋巴器官中S1P的浓度是如何被调节的。

The signaling lipid sphingosine-1-phosphate (S1P) plays critical roles in mammalian biology. The concentration of S1P is high in blood, and plasma S1P stabilizes junctions between vascular endothelial cells. The concentration of S1P is low in lymphoid tissues compared to blood and lymph, and S1P compartmentalization is required to maintain proper lymphocyte circulation. Although S1P in lymphoid organs is low in homeostasis, the concentration of S1P may increase upon inflammation, and increases in tissue S1P have been reported to promote angiogenesis and to enhance pro-inflammatory responses of innate and adaptive immune cells. Drugs targeting S1P signaling and S1P metabolism are currently in clinical trials as immune suppressants. By blocking lymphocyte exit from lymphoid organs, these drugs prevent activated T cells from reaching transplanted organs or organs that are subject to autoimmune attack. These drugs may also have direct anti-inflammatory effects. Despite S1P's vital functions, little is understood about how its distribution is controlled. To maintain low tissue S1P, two sources must be contained. First, tissues are constantly bathed with plasma to bring nourishment and remove waste. Plasma S1P must be prevented from entering, or removed from, the organs. Second, all cells are thought to make S1P intracellularly during the course of membrane sphingolipid metabolism. This intracellular S1P must be destroyed before it is secreted into the interstitial space. This grant investigates how S1P concentrations in the lymphoid organs are regulated.