Modulation of innate and adaptive immunity by sphingosylphosphorylcholine

鞘磷脂在多种不同的免疫功能中起着重要作用，如淋巴细胞迁移和激活、胸腺细胞成熟和抗原呈递。1-磷酸鞘氨醇(S1P)和S1P受体是这些免疫细胞功能的重要介质。为了研究鞘磷脂代谢改变对免疫监测和传染病的影响，并发现治疗干预的新策略，将分析酸性鞘磷脂酶(SMPD1-/-)缺陷小鼠由于其鞘脂组成严重受损而导致的免疫功能改变。主要集中在三个方面的研究：(1)鞘糖磷酰胆碱(SPC)作为信号分子通过S1P和孤儿受体的评价；(2)分泌溶血磷脂酶D的自体趋化蛋白(ATX)作为活性信号分子在S1P产生中的作用；(3)受损的分泌途径对S1P和SPC释放的影响。基础生化调查将与免疫功能改变的分析相结合，特别是淋巴细胞循环、T细胞发育和抗原呈递。主要的S1P降解酶S1P裂解酶和分泌的溶血磷脂酶D ATX的抑制剂将改变S1P和相关生物活性鞘脂的可用性。这些研究将最终证明S1P和其他鞘磷脂代谢物对不同免疫细胞功能的作用，并为免疫干预的新治疗策略提供关键知识。

Sphingolipids play an important role for several different immune functions like lymphocyte migration and activation, thymocyte maturation, and antigen presentation. Sphingosine 1-phosphate (S1P) and S1P receptors are important mediators for these immune cell functions. To investigate the impact of altered sphingolipid metabolism for immune surveillance and infectious diseases, and to discover novel strategies for therapeutic interventions, mice deficient for the acid sphingomyelinase (Smpd1-/-) will be analyzed with regard to their altered immune functions due to their severely impaired sphingolipid composition. The main focus will be the investigation of three different aspects: (1) The evaluation of sphingosylphosphorylcholine (SPC) as a signaling molecule via S1P and orphan receptors, (2) The role of autotaxin (ATX), a secreted lysophospholipase D, for the generation of S1P as an active signaling molecule, and (3) the influence of the impaired secretory pathway for the release of S1P and SPC. The basic biochemical investigations will be combined with the analysis of altered immune functions, particularly lymphocyte circulation, T cell development, and antigen presentation. The availability of S1P and related bioactive sphingolipids will be altered with inhibitors for the major S1P-degrading enzyme S1P-lyase and the secreted lysophospholipase D ATX. These studies will ultimately demonstrate the role of S1P and other sphingolipid metabolites for diverse immune cell functions and provide critical knowledge for novel therapeutic strategies for immune interventions.