Ceramide-1-Phosphate: a new player in modulating DC in allergic airway inflammation!?

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Dendritic cells have been shown to be essential in the induction and maintenance of T helper 2 (TH2)-cell responses to inhaled allergens in asthma. Recent studies suggest that sphingolipid mediators (like ceramide, ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P)) are involved in regulating inflammation, via intracellular signalling pathway and/or binding to specific plasma-membrane receptors. While the role of S1P in the pathogenesis of asthma and DC biology has been extensively studied, little is know about C1P. Preliminary data by our group revealed that C1P might exert anti-inflammatory effects in acute allergic airway inflammation via modulation DC function. In the present study we want to investigate whether: 1) C1P can inhibit all cardinal features of acute and chronic experimental asthma; 2) C1P modulates the maturation, cytokine production and T cell priming capacity of bone marrow derived DC in vitro and in vivo 3) C1P effects the migration and TH2-priming of endogenous DC in vivo; 4) C1P influences maturation, cytokine production and T cell priming of human monocyte derived DC-function. 5) Does C1P interact with ORMDL-expression? 6) Finally, is C1P able to inhibit allergic airway inflammation in general and DC-driven humanized SCID-mouse model of asthma. This project will elucidate the role of C1P on DC-function in asthma.