Sphingosine 1-phosphate receptor 1signaling in macrophages reduces atherosclerosis in LDL receptor-deficient mice.

Autor: Potì F; Unit of Neuroscience, Department of Medicine and Surgery, University of Parma, Parma, Italy.; Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy., Scalera E; Department of Food and Drug, University of Parma, Parma, Italy.; Central Laboratory Facility, University Hospital Münster, Münster, Germany., Feuerborn R; Central Laboratory Facility, University Hospital Münster, Münster, Germany., Fischer J; Institute of Molecular Tumor Biology, University of Münster, Münster, Germany., Arndt L; Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Germany., Varga G; Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany., Pardali E; Department of Cardiology, University Hospital Münster, Münster, Germany.; Pharvaris GmbH, Zug, Switzerland., Seidl MD; Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany., Fobker M; Central Laboratory Facility, University Hospital Münster, Münster, Germany., Liebisch G; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany., Hesse B; Division of General Internal Medicine, Nephrology, and Rheumatology, Department of Medicine D, and., Lukasz AH; Division of General Internal Medicine, Nephrology, and Rheumatology, Department of Medicine D, and., Rossaint J; Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany., Kehrel BE; Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany., Rosenbauer F; Institute of Molecular Tumor Biology, University of Münster, Münster, Germany., Renné T; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.; Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany., Christoffersen C; Department of Clinical Biochemistry, Rigshospitalet, and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Simoni M; Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy., Burkhardt R; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany., Nofer JR; Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy.; Central Laboratory Facility, University Hospital Münster, Münster, Germany.; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Institute for Laboratory Medicine, Marien-Hospital, Niels-Stensen-Kliniken, Osnabrück, Germany.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 Dec 20; Vol. 9 (24). Date of Electronic Publication: 2024 Dec 20.
DOI: 10.1172/jci.insight.158127
Abstrakt: 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.
Databáze: MEDLINE