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Updated: Jun 7, 2025
A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Sphingosine 1-phosphate receptor 1signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice
Francesco Potì1,2, Enrica Scalera3,4, Renata Feuerborn4
1Unit of Neuroscience, Department of Medicine and Surgery, University of Parma, Parma, Italy.
Abstract:
Sphingosine 1-phosphate (S1P) is a lysosphingolipid with antiatherogenic properties, but mechanisms underlying its effects remain unclear. We here investigated atherosclerosis development in cholesterol-rich diet-fed LDL receptor-deficient mice with high or low overexpression levels of S1P receptor 1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.1, interferon regulatory factor 8 (IRF8), and liver X receptor (LXR) and were skewed toward an M2-distinct phenotype characterized by enhanced production of IL-10, IL-1RA, and IL-5; increased ATP-binding cassette transporter A1- and G1-dependent cholesterol efflux; increased expression of MerTK and efferocytosis; and reduced apoptosis due to elevated B cell lymphoma 6 and Maf bZIP B. A similar macrophage phenotype was observed in mice administered S1P1-selective agonist KRP203. Mechanistically, the enhanced PU.1, IRF8, and LXR activity in S1P1-overexpressing macrophages led to downregulation of the cAMP-dependent PKA and activation of the signaling cascade encompassing protein kinases AKT and mTOR complex 1 as well as the late endosomal/lysosomal adaptor MAPK and mTOR activator 1. Atherosclerotic lesions in aortic roots and brachiocephalic arteries were profoundly or moderately reduced in mice with high and low S1P1 overexpression in macrophages, respectively. We conclude that S1P1 signaling polarizes macrophages toward an antiatherogenic functional phenotype and countervails the development of atherosclerosis in mice.
Insights
Sphingosine 1-phosphate receptor 1 (S1P1) signaling in macrophages promotes an antiatherogenic M2 phenotype. This polarization reduces atherosclerotic lesion development in mice, revealing a novel therapeutic mechanism for cardiovascular disease.
Area of Science:
- Immunology
- Cardiovascular Research
- Molecular Biology
Background:
- Sphingosine 1-phosphate (S1P) is a bioactive lipid with known antiatherogenic effects.
- The precise molecular mechanisms by which S1P exerts its protective functions against atherosclerosis are not fully understood.
- Macrophage polarization plays a critical role in the development and progression of atherosclerotic lesions.
Purpose of the Study:
- To investigate the role of Sphingosine 1-phosphate receptor 1 (S1P1) in macrophages during atherosclerosis development.
- To elucidate the molecular mechanisms by which S1P1 signaling influences macrophage phenotype and function.
- To evaluate the therapeutic potential of modulating S1P1 activity in preventing atherosclerosis.
Main Methods:
- Utilized LDL receptor-deficient mice fed a cholesterol-rich diet, with varying levels of S1P1 overexpression in macrophages.
- Administered a selective S1P1 agonist (KRP203) to assess its impact on macrophage phenotype.
- Analyzed gene expression, transcription factor activity (PU.1, IRF8, LXR), M2 macrophage markers, cholesterol efflux, efferocytosis, and apoptosis.
- Investigated downstream signaling pathways including PKA, AKT, and mTOR complex 1.
Main Results:
- S1P1 overexpression in macrophages skewed them towards an M2-like phenotype, characterized by increased IL-10, IL-1RA, and IL-5 production.
- S1P1-overexpressing macrophages exhibited enhanced cholesterol efflux, efferocytosis, and reduced apoptosis.
- S1P1 signaling modulated transcription factor activity and downstream signaling pathways (AKT, mTORC1).
- Administration of an S1P1 agonist mimicked these beneficial macrophage changes.
- Significant reduction in atherosclerotic lesion size was observed in mice with S1P1-overexpressing macrophages.
Conclusions:
- S1P1 signaling in macrophages is a key driver of antiatherogenic M2 polarization.
- Modulation of S1P1 activity represents a promising therapeutic strategy for mitigating atherosclerosis.
- The study reveals novel molecular targets and pathways involved in S1P-mediated protection against cardiovascular disease.
