Poti, Francesco and Scalera, Enrica and Feuerborn, Renata and Fischer, Josephine and Arndt, Lilli and Varga, Georg and Pardali, Evangelia and Seidl, Matthias D. and Fobker, Manfred and Liebisch, Gerhard and Hesse, Bettina and Lukasz, Alexander H. and Rossaint, Jan and Kehrel, Beate E. and Rosenbauer, Frank and Renne, Thomas and Christoffersen, Christina and Simoni, Manuela and Burkhardt, Ralph and Nofer, Jerzy-Roch (2024) Sphingosine 1-phosphate receptor 1 signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice. JCI INSIGHT, 9 (24): e158127. ISSN , 2379-3708
Full text not available from this repository. (Request a copy)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 receptor1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.1, interferon regulatory factor 8 (IRF8), and liverX 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 cAMPdependent 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | APOLIPOPROTEIN M; AMELIORATES ATHEROSCLEROSIS; SPHINGOSINE-1-PHOSPHATE; POLARIZATION; INFLAMMATION; ACTIVATION; PU.1; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Dec 2025 06:36 |
| Last Modified: | 09 Dec 2025 06:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65067 |
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