|
The current knowledge of allergic inflammation rests largely on mast cells, basophils and eosinophils as the pro-inflammatory mediators. However, increasing evidence shows that neutrophils can form the main population recruited during allergic inflammation and are the primary perpetrators of the more severe, and difficult to manage forms of this disease. We have in vitro and in vivo data showing that in response to histamine, the vasculature rapidly expresses the adhesion molecule P-selectin causing immediate neutrophil recruitment. Our studies show that this mechanism is controlled by the lipid enzyme sphingosine kinase (SK)1. Fingolimod is an FDA approved pro-drug currently used to treat multiple sclerosis; but it can also inhibit SK1 activity. Using two allergic inflammatory animal models, one induced by histamine and the other immunoglobulin (Ig)-E mediated in a setting of passive cutaneous anaphylaxis we reveal that topical application of Fingolimod can effectively prevent allergic immune responses in mice. Fingolimod attenuates SK1, but not SK2 activity, to cause reduction in the levels of pro-inflammatory chemoattractants and neutrophil flux at the inflammatory site. More importantly, topical application of Fingolimod results in a sustained therapeutic effect compared to similar administration of anti-histamines. Preliminary data in a pre-clinical human skin prick test trial support our animal models. Briefly, topical application of Fingolimod attenuates histamine-induced and allergen-induced allergic responses in the forearms of healthy participants. Taken together, our work suggests that SK may be a new target to prevent and regulate pathological neutrophil recruitment during allergic inflammation and as such may be a new treatment option for acute and fatal allergic diseases. Moreover, our results suggest a new indication for Fingolimod in that it may be valuable in the treatment of these debilitating diseases. |