Modulation of innate and adaptive immunity by sphingosylphosphorylcholine

鞘脂对几种不同的免疫功能如淋巴细胞迁移和活化、胸腺细胞成熟和抗原呈递起重要作用。鞘氨醇1-磷酸（S1 P）和S1 P受体是这些免疫细胞功能的重要介质。为了研究鞘脂代谢改变对免疫监视和感染性疾病的影响，并发现新的治疗干预策略，将分析酸性鞘磷脂酶（Smpd 1-/-）缺陷小鼠由于鞘脂组成严重受损而改变的免疫功能。主要关注三个不同方面的研究：（1）鞘氨醇磷酸胆碱（SPC）作为通过S1 P和孤儿受体的信号分子的评价，（2）自分泌运动因子（ATX），一种分泌型溶血磷脂酶D，作为活性信号分子的S1 P的产生的作用，和（3）受损的分泌途径对S1 P和SPC释放的影响。基本的生物化学研究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。S1 P和相关生物活性鞘脂的可用性将被主要S1 P降解酶S1 P-裂解酶和分泌的溶血磷脂酶D ATX的抑制剂改变。这些研究将最终证明S1 P和其他鞘脂代谢物对不同免疫细胞功能的作用，并为免疫干预的新型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.