Sphingosine-1-phosphate (S1P) and its receptors have been implicated in functions of Langerhans cells and
atopic dermatitis. In this study, we investigated the roles of
S1P receptor type 2 (S1P2) in a mouse model of
atopic dermatitis, which was induced by topical application of
2,4-dinitrochlorobenzene (
DNCB) on ventral skin on D0, followed by repeated
DNCB challenge on both ears from D7 to D49. Wild-type mice with
atopic dermatitis displayed severe
inflammation and mast cell accumulation in ear tissues and elevated
IgE levels in serum. Furthermore, the mice showed significantly increased sizes of draining lymph nodes, high levels of inflammatory
cytokines (IL-4, IL-13, IL-17, and IFN-γ) in the ears and lymph nodes and high levels of
chemokines CCL17 and CCL22 in ears. Administration of
JTE-013, a selective antagonist of S1P2 (3 mg/kg, i.p, from D19 to D49) before
DNCB challenge significantly suppressed
DNCB-induced atopic responses in ears and lymph nodes.
JTE-013 administration also significantly decreased the lymph nodes sizes, the levels of inflammatory
cytokines (IL-4, IL-13, IL-17, and IFN-γ) in the ears and lymph nodes, and the levels of
chemokines CCL17 and CCL22 in ears. Furthermore, the inflammatory responses of
atopic dermatitis were greatly ameliorated in S1pr2 gene-deficient mice. As CCL17 and CCL22 are CCR4
ligands, acting as Th2-attracting
chemokines, we investigated CCL17 and CCL22 expression in bone marrow-derived dendritic cells (BMDCs) from wild-type and S1pr2 gene-deficient mice. Addition of
IL-4 (10 ng/mL) markedly increased the levels of CCL17 and CCL22, but IL-4-induced CCL17 and CCL22 expression was significantly blunted in BMDCs from S1pr2 gene-deficient mice. Furthermore, pretreatment with
JTE-013 (1-30 μM) dose-dependently suppressed this induction in BMDCs from wild-type mice. Our results demonstrate that blockage of S1P2 ameliorates not only
DNCB-induced
atopic dermatitis symptoms but also Th2 cell-attracting capacity of dendritic cells, suggesting S1P2 as a potential therapeutic target for
atopic dermatitis.