Abstract
Sphingosine-1-phosphate and its receptors have emerged as important modulators of the immune response. The sphingosine-1-phosphate pro-drug FTY720 can alleviate experimental allergic airway inflammation. Nevertheless, the role of individual sphingosine-1-phosphate receptors in the regulation of allergic airway inflammation remains undefined. Using a newly characterized potent and selective sphingosine-1-phosphate receptor 1 (S1P1) agonist with physical properties allowing airway delivery, we studied to the contribution of S1P1 signaling to eosinophilic airway inflammation induced in ovalbumin-immunized mice by airway challenges with ovalbumin. Airways delivery of receptor-non-selective sphingosine-1-phosphate pro-drug significantly inhibits the sequential accumulation of antigen presenting dendritic cells and CD4+ T cells in draining lymph nodes. This in turn suppressed by >80% the accumulation of CD4+ T cell and eosinophils in the airways. Systemic delivery of sphingosine-1-phosphate pro-drug or of an S1P1-specific agonist at doses sufficient to induce lymphopenia did not inhibit eosinophil accumulation in the airways. In contrast, local airway delivery of S1P1-specific agonist inhibited airways release of endogenous CCL5 and CCL17 chemokines, and significantly suppressed accumulation of activated T cells and eosinophils in the lungs. Specific S1P1 agonism in lungs contributes significantly to anti-inflammatory activities of sphingosine-1-phosphate therapeutics by suppressing chemokine release in the airways, and may be of clinical relevance.
- Received June 9, 2010.
- Revision received October 6, 2010.
- Accepted October 7, 2010.
- The American Society for Pharmacology and Experimental Therapeutics