Sphingosine 1-phosphate (S1P), which acts via G protein-coupled S1P receptors (S1PRs), is a bioactive lipid essential for vascular integrity and lymphocyte trafficking. The S1P–S1PR signalling axis is a key component of the inflammatory response in autoimmune rheumatic diseases. Several drugs that target S1PRs have been approved for the treatment of multiple sclerosis and inflammatory bowel disease and are under clinical testing for patients with systemic lupus erythematosus (SLE). Preclinical studies support the hypothesis that targeting the S1P–S1PR axis would be beneficial to patients with SLE, rheumatoid arthritis (RA) and systemic sclerosis (SSc) by reducing pathological inflammation. Whereas most preclinical research and development efforts are focused on reducing lymphocyte trafficking, protective effects of circulating S1P on endothelial S1PRs, which maintain the vascular barrier and enable blood circulation while dampening leukocyte extravasation, have been largely overlooked. In this Review, we take a holistic view of S1P–S1PR signalling in lymphocyte and vascular pathobiology. We focus on the potential of S1PR modulators for the treatment of SLE, RA and SSc and summarize the rationale, pathobiology and evidence from preclinical models and clinical studies. Improved understanding of S1P pathobiology in autoimmune rheumatic diseases and S1PR therapeutic modulation is anticipated to lead to efficacious and safer management of these diseases.

1-磷酸鞘氨醇 (S1P) 通过 G 蛋白偶联 S1P 受体 (S1PR) 发挥作用，是一种对血管完整性和淋巴细胞运输至关重要的生物活性脂质。S1P–S1PR 信号轴是自身免疫性风湿病炎症反应的关键组成部分。几种靶向 S1PR 的药物已被批准用于治疗多发性硬化症和炎症性肠病，并且正在进行针对系统性红斑狼疮 (SLE) 患者的临床试验。临床前研究支持这样的假设，即靶向 S1P-S1PR 轴将通过减少病理性炎症对 SLE、类风湿性关节炎 (RA) 和系统性硬化症 (SSc) 患者有益。尽管大多数临床前研究和开发工作都集中在减少淋巴细胞运输上，循环 S1P 对内皮 S1PR 的保护作用在很大程度上被忽视了，内皮 S1PR 维持血管屏障并促进血液循环，同时抑制白细胞外渗。在这篇综述中，我们全面了解淋巴细胞和血管病理学中的 S1P–S1PR 信号传导。我们专注于 S1PR 调节剂治疗 SLE、RA 和 SSc 的潜力，并总结了临床前模型和临床研究的基本原理、病理生物学和证据。提高对自身免疫性风湿病 S1P 病理生物学和 S1PR 治疗调节的理解有望导致对这些疾病的有效和更安全的管理。我们全面了解淋巴细胞和血管病理学中的 S1P–S1PR 信号传导。我们专注于 S1PR 调节剂治疗 SLE、RA 和 SSc 的潜力，并总结了临床前模型和临床研究的基本原理、病理生物学和证据。提高对自身免疫性风湿病 S1P 病理生物学和 S1PR 治疗调节的理解有望导致对这些疾病的有效和更安全的管理。我们全面了解淋巴细胞和血管病理学中的 S1P–S1PR 信号传导。我们专注于 S1PR 调节剂治疗 SLE、RA 和 SSc 的潜力，并总结了临床前模型和临床研究的基本原理、病理生物学和证据。提高对自身免疫性风湿病 S1P 病理生物学和 S1PR 治疗调节的理解有望导致对这些疾病的有效和更安全的管理。