Blockage of sphingosine-1-phosphate receptor 2 attenuates allergic asthma in mice

Sphingosine-1-phosphate 2 (S1P₂ ) receptors have been implicated in degranulation of mast cells. However, functions of S1P₂ receptors have not been investigated in an in vivo model of allergic asthma.

Using an ovalbumin (OVA)-induced asthma model, the function of S1P₂ receptors was evaluated in S1P₂ -deficient mice or in mice treated with JTE-013, a selective S1P₂ antagonist. Bone marrow-derived dendritic cells (BMDCs) were used to investigate the roles of S1P₂ receptors in dendritic cell maturation and migration.

Eosinophil accumulation and elevated Th2 cytokine levels in bronchoalveolar lavage fluid and inflamed lung tissues were strongly inhibited by administration of JTE-013 before OVA sensitization, before OVA challenge, and before both events. In S1P₂ -deficient mice, allergic responses were significantly lower than in wild-type mice. LPS- and OVA-induced maturation of BMDCs was significantly blunted in dendritic cells from S1P₂ -deficient mice and by treatment with JTE-013. Migrations of immature and mature BMDCs were also dependent on S1P₂ receptors. It was found that OVA-challenged mice into which in vitro OVA primed BMDCs from S1P₂ -deficient mice were adoptively transferred, had less severe asthma responses than OVA-challenged mice into which OVA-primed BMDCs from wild-type mice were adoptively transferred.

Pro-allergic functions of S1P₂ receptors were elucidated in a murine asthma model. S1P₂ receptors were involved not only in maturation and migration of dendritic cells in the sensitization phase but also in mast cell degranulation in the challenge phase. These results suggest S1P₂ receptor as a therapeutic target for allergic asthma.