Inhibiting Sphingosine Kinase 2 Derived-sphingosine-1-phosphate Ameliorates Psoriasis-like Skin Disease via Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes in Mice
Sun-Hye Shin, Kyung-Ah Cho, Soojung Hahn, Younghay Lee, Yu-He Kim, So-Youn Woo, Kyung-Ha Ryu, Woo-Jae Park, Joo-Won Park
Sphingosine-1-phosphate (S1P) is a signalling sphingolipid metabolite that regulates important cell processes, including cell proliferation and apoptosis. Circulating S1P levels have been reported to be increased in patients with psoriasis relative to healthy patients. The aim of this study was to examine the potency of S1P inhibition using an imiquimod-induced psoriasis mouse model. Both topical ceramidase and sphingosine kinase 1/2 inhibition, which blocks S1P generation, alleviated imiquimod-induced skin lesions and reduced the serum interleukin 17-A levels induced by application of imiquimod. These treatments also normalized skin mRNA levels of genes associated with inflammation and keratinocyte differentiation. Inhibition of sphingosine kinase 2, but not sphingosine kinase 1, diminished levels of suppressor of cytokine signalling 1 and blocked T helper type 17 differentiation of naïve CD4+ T cells; imiquimod-induced psoriasis-like skin symptoms were also ameliorated. These results indicate the distinct effects of sphingosine kinase 1 and sphingosine kinase 2 inhibition on T helper type 17 generation and suggest molecules that inhibit S1P formation, including ceramidase and sphingosine kinase 2 inhibitors, as novel therapeutic candidates for psoriasis.
Sphingosine-1-phosphate is a bioactive lipid molecule involved in various cellular processes, such as cell proliferation and death. It can be formed by enzymes called sphingosine kinases. Elevation of sphingosine-1-phosphate in patients with psoriasis has been reported recently. Modulation of sphingolipids, including sphingsosine-1-phosphate, has emerged as a potentially powerful new clinical approach, and considerable progress has been made recently. Therefore, the effects of sphingosine-1-phosphate and its modulation on psoriasis should be assessed to uncover new therapeutic candidates for psoriasis. This study suggests molecules that inhibit sphingosine-1-phosphate formation, including ceramidase and sphingosine kinase 2 inhibitors, as novel therapeutic agents for psoriasis.