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

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Francesco Potì, Enrica Scalera, Renata Feuerborn, Josephine Fischer, Lilli Arndt, Georg Varga, Evangelia Pardali, Matthias D Seidl, Manfred Fobker, Gerhard Liebisch, Bettina Hesse, Alexander H Lukasz, Jan Rossaint, Beate E Kehrel, Frank Rosenbauer, Thomas Renné, Christina Christoffersen, Manuela Simoni, Ralph Burkhardt, Jerzy-Roch Nofer
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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.

巨噬细胞中的球蛋白-1-磷酸(S1P)受体 1 型信号可减少低密度脂蛋白受体缺陷小鼠的动脉粥样硬化。
1-phosphate (S1P) 是一种具有抗动脉粥样硬化特性的溶酶磷脂,但其作用机制仍不清楚。我们在此研究了巨噬细胞中S1P受体1型(S1P1)过表达水平高或低的富含胆固醇饮食喂养的低密度脂蛋白受体缺陷小鼠的动脉粥样硬化发展情况。S1P1过表达的巨噬细胞显示转录因子PU.1、IRF8和LXR的活性增加,并偏向于M2-distinct表型,其特点是IL-10、IL-1RA和IL-5的产生增加,ATP结合盒转运体A1和G1依赖性胆固醇外流增加,MerTK的表达和流出增加,Bcl6和MafB的升高导致细胞凋亡减少。在施用 S1P1 选择性激动剂 KRP203 的小鼠中也观察到了类似的巨噬细胞表型。从机理上讲,S1P1表达的巨噬细胞中PU.1、IRF8和LXR活性的增强导致了cAMP依赖性蛋白激酶A的下调,并激活了包括蛋白激酶Akt和mTOR复合体1(mTORC1)以及晚期内体/溶酶体适配体MAPK和mTOR激活剂1(Lamtor-1)在内的信号级联。巨噬细胞中高水平和低水平 S1P1 过表达的小鼠主动脉根部和肱动脉的动脉粥样硬化病变分别显著或适度减少。我们的结论是,S1P1 信号将巨噬细胞极化为抗动脉粥样硬化的功能表型,并逆转小鼠动脉粥样硬化的发展。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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