Acta Dermato-Venereologica 99-6CompleteContent | Page 18

594 INVESTIGATIVE REPORT 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 1# , Kyung-Ah CHO 2# , Soojung HAHN 1,3 , Younghay LEE 1 , Yu‑Hee KIM 2 , So-Youn WOO 2 , Kyung-Ha RYU 4 , Woo-Jae PARK 5 and Joo-Won PARK 1 Departments of 1 Biochemistry, 2 Microbiology and 4 Pediatrics, College of Medicine, Ewha Womans University, 3 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Graduate School, Sungkyunkwan University, Seoul, and 5 Department of Biochemistry, College of Medicine, Gachon University, Incheon, South Korea # These authors contributed equally to this manuscript. Sphingosine-1-phosphate (S1P) is a signalling sphingo­ lipid metabolite that regulates important cell proces- ses, including cell proliferation and apoptosis. Circula- ting 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 sphingosi- ne kinase 1/2 inhibition, which blocks S1P generation, alleviated imiquimod-induced skin lesions and reduced the serum interleukin 17-A levels induced by applica- tion of imiquimod. These treatments also normalized skin mRNA levels of genes associated with inflam- mation and keratinocyte differentiation. Inhibition of sphingosine kinase 2, but not sphingosine kinase 1, diminished levels of suppressor of cytokine signal- ling 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 ki- nase 2 inhibitors, as novel therapeutic candidates for psoriasis. Key words: psoriasis; CD4 + T lymphocyte; sphingosine kinase; sphingosine-1-phosphate; Th17 differentiation. Accepted Mar 4, 2019; E-published Mar 5, 2019 Acta Derm Venereol 2019; 99: 594–601. Corr: Joo-Won Park, Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07985, South Korea. E-mail: joowon. [email protected]; and Woo-Jae Park, Department of Biochemistry, Col- lege of Medicine, Gachon University, Incheon 21999, South Korea. E- mail: [email protected] P soriasis is a common, chronic immune-mediated inflammatory skin disorder (1). The important role of T-helper 17 (Th17) cells in the development of psoriasis lesions has been examined in many studies (2, 3). In patients with psoriasis, this unique CD4 + T-cell subset, characterized by interleukin-17 (IL-17) production, is found in the dermis of psoriasis lesions; the levels of circulating Th17 cells are also elevated (3, 4). IL-17A and IL-22 participate in the inflammatory process during doi: 10.2340/00015555-3160 Acta Derm Venereol 2019; 99: 594–601 SIGNIFICANCE Sphingosine-1-phosphate is a bioactive lipid molecule involved in various cellular processes, such as cell proli- feration and death. It can be formed by enzymes called sphingosine kinases. Elevation of sphingosine-1-phosphate in patients with psoriasis has been reported recently. Modu- lation of sphingolipids, including sphingsosine-1-phospha- te, has emerged as a potentially powerful new clinical ap- proach, 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. psoriasis by promoting the accumulation of T cells and neutrophils in the psoriatic lesion (5). Therapeutic ap- proaches that modulate Th17 cells or the effector cyto- kines they produce have shown some efficacy for the treatment of psoriasis (5). Sphingolipids are a complex group of lipids that contain the long-chain bases sphinganine (dihydrosp- hingosine) and sphingosine. Attaching fatty acyl CoA to a long-chain base via an amide linkage generates ceramide (Fig. S1 1 ), which can be modified further to produce more complex sphingolipids (e.g. sphingomyelins, cerebrosi- des, and gangliosides) (6). Sphingolipids have structural roles in lipid membranes and can also serve as sources of signalling molecules (7, 8). Signalling pathways affected by sphingolipids and their derivatives include those as- sociated with apoptosis, proliferation, inflammation, and mitochondrial function (7, 8). Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cell processes (8). It can be formed by sphingosine kinases (SKs), which catalyse the phospho- rylation of sphingosine. There are 2 types of SKs; SK1 is in the cytosol and plasma membrane and SK2 is in the nucleus (9). Although SK1 and SK2 share 80% si- milarity and 45% overall sequence identity, each has a https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3160 1 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.