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

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*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

4 Downloads (Pure)

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.

OriginalsprogEngelsk
Artikelnummere158127
TidsskriftJCI insight
Vol/bind9
Udgave nummer24
Antal sider18
ISSN2379-3708
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This project was supported by grants NO406/3-1 and BU2263/3-1 from Deutsche Forschungsgemeinschaft (DFG) to JRN and RB, DFG \u2014 Project number 209933838 \u2014 Collaborative Research Center 1052 \u201CObesity Mechanisms\u201D (SFB-1052/B07) to RB, grant IDEAS RBID08777T from the Italian Ministry of Education, Universities and Research to JRN and MS and grants GR-2011-02346974 from the Italian Ministry of Health and FIL2016-competitive section from the University of Parma to FP. The expert technical assistance of Beate Schulte, Cornelia Richter-Elsenheimer, and B\u00E4rbel Schell is gratefully acknowledged.

Publisher Copyright:
Copyright: © 2024, Potì et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Citationsformater