Inhibition of Sphingosine-1-Phosphate Receptor 2 (S1P(2)) Attenuates Imiquimod-Induced Psoriasis-Like Skin Inflammation in BALB/c Mice.

Serum and epidermal levels of sphingosine 1-phosphate (S1P) are higher in patients with psoriasis than healthy subjects. Although roles of type 1 S1P receptor, S1P(1), in the development of psoriasis has intensively been investigated, roles of S1P(2) have not been elucidated. We aim to investigate whether blockage of S1P(2) reduce imiquimod-induced psoriasis-like dermatitis using an S1P(2) antagonist, JTE-013, in combination with S1pr2 wild-type (WT) and knock-out (KO) BALB/c mice. Imiquimod induced increase of erythematous papules and plaques with silver scaling, whereas administration of JTE-013 significantly suppressed those increases in S1pr2 WT mice. Deficiency of S1pr2 gene reduced the imiquimod-induced symptoms. Imiquimod increased mRNA expression levels of pro-inflammatory Th1/Th17 cytokines, whereas JTE-013 significantly suppressed those increases in S1pr2 WT mice. Deficiency of S1pr2 gene also suppressed the imiquimod-induced pro-inflammatory cytokine expression. Imiquimod induced enlargement of lymph nodes and spleens, whereas JTE-013 suppressed them in S1pr2 WT mice. Imiquimod induced increase of pro-inflammatory Th1/Th17 cytokine levels and Th17 cell numbers in lymph nodes and spleens, whereas JTE-013 suppressed them in S1pr2 WT mice. In summary, the present results suggest that blockage of S1P(2) could suppress the characteristics of psoriasis-form dermatitis and be a therapeutic strategy.