siRNA knockdown of SPHK1 in vivo protects mice from systemic, type-I Allergy

Systemic anaphylaxis is considered to be a typical immediate hypersensitivity response, determined by the activation of immune cells,via antigen-induced aggregation of IgE-sensitized FcεRI cells. Perhaps most the important cells, in the immediate hypersensitivity responses, are mast cells. We have previously shown that SPHK1 plays a key role in the intracellular signaling pathways triggered by FceRI aggregation on humanmast cells. More recently, we performed a genome-wide gene expression profiling of human mast cells, sensitized with IgE alone, or stimulated by FcεRI aggregation. We found that sphingosine kinase 1 (SPHK1) was oneof genes activated at the earlier stages of mast cell activation, including during sensitization. Moreover, SPHK1 has been shown, by us and others, to be a key player in the intracellular signaling pathways triggered byseveral immune-receptors, including fMLP, C5a, and Fcg- and Fcereceptors. Here we have investigated the in vivo role of SPHK1 in allergy, using a specific siRNA to knockdown SPHK1 in vivo. Our results support a role forSPHK1 in the inflammatory responses that share clinical, immunological, and histological features of type I hypersensitivity. Thus, mice pretreated with the siRNA for SPHK1 were protected from the IgE mediated allergicreactions including: temperature changes, histamine release, cytokine production, cell-adhesion molecule expression, and immune cell infiltration into the lungs.