Inhibition of sphingosine 1-phosphate lyase activates human keratinocyte differentiation and attenuates psoriasis in mice[S]
Inhibition of sphingosine 1-phosphate lyase activates human keratinocyte differentiation and attenuates psoriasis in mice[S]
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DOI：
10.1194/jlr.ra119000254
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发表时间：
2020-01-01
影响因子：
6.5
通讯作者：
Park, Tae-Sik
中科院分区：
文献类型：
--
作者：
Jeon, Suwon;Song, Jaehwi;Park, Tae-Sik
1-磷酸鞘氨醇(S1P)裂解酶是一种催化S1P不可逆降解的胞内酶，已被认为是治疗寻常型银屑病的靶点。由于S1P诱导角质形成细胞分化，我们研究了S1P裂解酶的调节和细胞内S1P水平的改变是否调节了人新生儿表皮角质形成细胞(HEKn)的增殖和分化。为了确定S1P裂解酶在皮肤中的生理功能，我们用S1P裂解酶特异性抑制剂(SLI)和S1P裂解酶1(SGPL1)特异性siRNA(SiSGPL1)抑制HEKn细胞中的S1P裂解酶。在HEKn细胞中，SLI的药物治疗通过上调p21和p27而导致G1期停滞，并诱导早期分化标志物角蛋白1。同样，siSGPL1的基因抑制使细胞周期停滞在G1期，并激活了分化。此外，siSGPL1的酶抑制作用上调了角蛋白1和分化标记物，包括总状蛋白和氯化蛋白。当IL-17和IL-22诱导HEKn细胞过度增殖时，SLI对S1P裂解酶的药理抑制作用可同时抑制HEKn细胞的增殖和激活其分化。此外，SLI治疗可在体内改善咪喹莫特引起的银屑病症状，包括红斑、鳞屑和表皮厚度。因此，我们证明抑制S1P裂解酶抑制细胞增殖和诱导角质形成细胞分化，并且抑制可能减轻银屑病样变。总之，这些发现表明S1P裂解酶是增殖和分化的调节因子，并支持其作为银屑病角质形成细胞治疗靶点的潜力。
Sphingosine 1-phosphate (S1P) lyase is an intracellular enzyme that catalyzes the irreversible degradation of S1P and has been suggested as a therapeutic target for the treatment of psoriasis vulgaris. Because S1P induces differentiation of keratinocytes, we examined whether modulation of S1P lyase and altered intracellular S1P levels regulate proliferation and differentiation of human neonatal epidermal keratinocyte (HEKn) cells. To identify the physiological functions of S1P lyase in skin, we inhibited S1P lyase in HEKn cells with an S1P lyase-specific inhibitor (SLI) and with S1P lyase 1 (SGPL1)-specific siRNA (siSGPL1). In HEKn cells, pharmacological treatment with the SLI caused G1 arrest by upregulation of p21 and p27 and induced keratin 1, an early differentiation marker. Similarly, genetic suppression by siSGPL1 arrested the cell cycle at the G1 phase and activated differentiation. In addition, enzyme suppression by siSGPL1 upregulated keratin 1 and differentiation markers including involucrin and loricrin. When hyperproliferation of HEKn cells was induced by interleukin (IL)-17 and IL-22, pharmacologic inhibition of S1P lyase by SLI decreased proliferation and activated differentiation of HEKn cells simultaneously. In addition, SLI administration ameliorated imiquimod-induced psoriatic symptoms including erythema, scaling, and epidermal thickness in vivo. We thus demonstrated that S1P lyase inhibition reduces cell proliferation and induces keratinocyte differentiation, and that inhibition may attenuate psoriasiform changes. Collectively, these findings suggest that S1P lyase is a modulating factor for proliferation and differentiation, and support its potential as a therapeutic target for psoriasis in human keratinocytes.