Zou Fei, Wang Su, Xu Mengmeng, Wu Zengrong, Deng Feihong
Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Research Center of Digestive Disease, Central South University, Changsha, Hunan, China.
Front Physiol. 2023 Jul 25;14:1235656. doi: 10.3389/fphys.2023.1235656. eCollection 2023.
Sphingosine-1-phosphate (S1P), a type of bioactive sphingolipid, can regulate various cellular functions of distinct cell types in the human body. S1P is generated intracellularly by the catalysis of sphingosine kinase 1/2 (SphK1/2). S1P is transferred to the extracellular environment via the S1P transporter, binds to cellular S1P receptors (S1PRs) and subsequently activates S1P-S1PR downstream signaling. Dysbiosis of the intestinal microbiota, immune dysregulation and damage to epithelial barriers are associated with inflammatory bowel disease (IBD). Generally, S1P mainly exerts a proinflammatory effect by binding to S1PR1 on lymphocytes to facilitate lymphocyte migration to inflamed tissues, and increased S1P was found in the intestinal mucosa of IBD patients. Notably, there is an interaction between the distribution of gut bacteria and SphK-S1P signaling in the intestinal epithelium. S1P-S1PR signaling can also regulate the functions of intestinal epithelial cells (IECs) in mucosa, including cell proliferation and apoptosis. Additionally, increased S1P in immune cells of the lamina propria aggravates the inflammatory response by increasing the production of proinflammatory cytokines. Several novel drugs targeted at S1PRs have recently been used for IBD treatment. This review provides an overview of the S1P-S1PR signaling pathway and, in particular, summarizes the various roles of S1P in the gut mucosal microenvironment to deeply explore the function of S1P-S1PR signaling during intestinal inflammation and, more importantly, to identify potential therapeutic targets for IBD in the SphK-S1P-S1PR axis.
鞘氨醇-1-磷酸（S1P）是一种生物活性鞘脂，可调节人体中不同细胞类型的各种细胞功能。S1P由鞘氨醇激酶1/2（SphK1/2）催化在细胞内生成。S1P通过S1P转运蛋白转移到细胞外环境，与细胞S1P受体（S1PRs）结合，随后激活S1P-S1PR下游信号传导。肠道微生物群失调、免疫调节异常和上皮屏障受损与炎症性肠病（IBD）相关。一般来说，S1P主要通过与淋巴细胞上的S1PR1结合发挥促炎作用，以促进淋巴细胞迁移至炎症组织，并且在IBD患者的肠道黏膜中发现S1P增加。值得注意的是，肠道细菌分布与肠道上皮中的SphK-S1P信号传导之间存在相互作用。S1P-S1PR信号传导还可调节黏膜中肠道上皮细胞（IECs）的功能，包括细胞增殖和凋亡。此外，固有层免疫细胞中S1P增加通过增加促炎细胞因子的产生加重炎症反应。最近，几种针对S1PRs的新型药物已用于IBD治疗。本综述概述了S1P-S1PR信号通路，特别是总结了S1P在肠道黏膜微环境中的各种作用，以深入探讨肠道炎症期间S1P-S1PR信号传导的功能，更重要的是，确定SphK-S1P-S1PR轴中IBD的潜在治疗靶点。
