Modulation of innate and adaptive immunity by sphingosylphosphorylcholine

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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.