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

• DOI: 10.1172/jci.insight.158127
• Publication Date: 2024-11-12T17:00:40Z
• Authors: 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 Christo...; Manuela Simoni; Ralph Burkhardt; Jerzy-Roch Nofer
• Keywords: Sphingosine-1-phosphate receptor

Sphingosine 1-phosphate (S1P) is a lysosphingolipid with anti-atherogenic properties, but mechanisms underlying its effects remain unclear. We here investigated atherosclerosis development in cholesterol-rich diet-fed LDL receptor-deficient mice high or low overexpression levels of S1P receptor type 1 (S1P1) macrophages. S1P1-overexpressing macrophages showed increased activity transcription factors PU.1, IRF8, and LXR were skewed towards M2-distinct phenotype characterized by enhanced production IL-10, IL-1RA, IL-5, ATP-binding cassette transporter A1- G1-dependent cholesterol efflux, expression MerTK efferocytosis, reduced apoptosis due to elevated Bcl6 MafB. A similar macrophage was observed administered S1P1-selective agonist KRP203. Mechanistically, the led down-regulation cAMP-dependent protein kinase activation signaling cascade encompassing kinases Akt mTOR complex (mTORC1) as well late endosomal/lysosomal adaptor MAPK activator (Lamtor-1). Atherosclerotic lesions aortic roots brachiocephalic arteries profoundly moderately S1P1 macrophages, respectively. conclude that polarizes an functional countervails mice.