Abstract
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.
Key points
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Autoimmune rheumatic diseases are complex and heterogeneous diseases that have fundamental pathophysiological pathways in common.
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These dysregulated pathways include lymphocyte autoreactivity, myeloid and endothelial cell activation, and extravasation of inflammatory mediators into tissues.
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Chronic inflammatory damage in autoimmune rheumatic disease leads to end organ damage.
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Sphingosine 1-phosphate receptor 1 (S1PR1) is expressed on leukocytes and endothelial cells and is an important mediator of lymphocyte trafficking, regulatory T/T helper 17 cell homeostasis and vascular permeability.
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Use of S1PR1 modulators in preclinical studies of systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis has shown promise in attenuating inflammatory injury and end organ damage.
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Modulation of S1PR1 signalling in leukocytes and/or endothelial cells warrants further evaluation in clinical studies in autoimmune rheumatic diseases.
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T.H. declares the following potential competing interests in 2021–2022: consultancy — Arena Pharmaceuticals, Bristol Myers-Squibb Inc., Janssen Inc; inventor — patents on ApoM-Fc, S1PR2 modulators; speakers fees — Pfizer Inc. The other authors declare no competing interests.
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Burg, N., Salmon, J.E. & Hla, T. Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases. Nat Rev Rheumatol 18, 335–351 (2022). https://doi.org/10.1038/s41584-022-00784-6
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DOI: https://doi.org/10.1038/s41584-022-00784-6
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