Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
J Invest Dermatol. 2019 Aug;139(8):1743-1752.e5. doi: 10.1016/j.jid.2019.02.010. Epub 2019 Feb 23.
Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator generated when a cell membrane or its components are damaged by various factors. S1P regulates diverse cell activities via S1P receptors (S1PRs). Keratinocytes express S1PR1-5. Although it is known that S1PRs control keratinocyte differentiation, apoptosis, and wound healing, S1PR functions in keratinocyte infections have not been fully elucidated. We propose that the S1P-S1PR axis in keratinocytes works as a biosensor for bacterial invasion. Indeed, in human impetigo infection, we found high epidermal expression of S1PR1 and S1PR2 in the skin. Furthermore, in normal human epidermal keratinocytes in vitro, treatment with Staphylococcus aureus bacterial supernatant not only induced S1P production but also increased the transcription of S1PR2, confirming our in vivo observation, as well as increased the levels of TNFA, IL36G, IL6, and IL8 mRNAs. However, direct treatment of normal human epidermal keratinocytes with S1P increased the expressions of IL36G, TNFA, and IL8, but not IL6. In both S1P- and S. aureus bacterial supernatant-treated normal human epidermal keratinocytes, S1PR1 knockdown reduced IL36G, TNFA, and IL8 transcription, and the S1PR2 antagonist JTE013 blocked the secretion of these cytokines. Overall, we have proven that during infections, keratinocytes communicate damage by using S1P release and tight control of S1PR1 and 2.
鞘氨醇 1-磷酸（S1P）是一种生物活性脂质介质，当细胞膜或其成分受到各种因素的损伤时会产生。S1P 通过 S1P 受体（S1PRs）调节多种细胞活动。角质形成细胞表达 S1PR1-5。虽然已知 S1PRs 控制角质形成细胞分化、凋亡和伤口愈合，但 S1PR 在角质形成细胞感染中的功能尚未完全阐明。我们提出角质细胞中的 S1P-S1PR 轴作为细菌入侵的生物传感器。事实上，在人类脓疱疮感染中，我们发现在皮肤中表皮高表达 S1PR1 和 S1PR2。此外，在体外正常的人表皮角质形成细胞中，金黄色葡萄球菌细菌上清液处理不仅诱导 S1P 产生，而且增加 S1PR2 的转录，证实了我们的体内观察结果，以及增加 TNFA、IL36G、IL6 和 IL8 mRNAs 的水平。然而，直接用 S1P 处理正常人表皮角质形成细胞会增加 IL36G、TNFA 和 IL8 的表达，但不会增加 IL6。在 S1P 和金黄色葡萄球菌细菌上清液处理的正常人表皮角质形成细胞中，S1PR1 敲低减少了 IL36G、TNFA 和 IL8 的转录，而 S1PR2 拮抗剂 JTE013 阻断了这些细胞因子的分泌。总的来说，我们已经证明，在感染过程中，角质形成细胞通过释放 S1P 并严格控制 S1PR1 和 S1PR2 来传递损伤信号。
