Francesco Potì, Italy
University of Parma Medicine and SurgeryPresenter of 1 Presentation
Sphingosine 1-phosphate (S1P) receptor type 1 signaling induces an anti-atherogenic phenotype in macrophages and attenuates atherosclerosis in LDL-receptor-deficient mice
Abstract
Background and Aims
Sphingosine 1-phosphate (S1P) accounts for antiatherogenic properties of high-density lipoproteins, but the S1P receptor subtype mediating the atheroprotective effects of S1P and the underlying molecular mechanisms remain enigmatic. Experimental models engineered to amplify the signaling of endogenous S1P over its specific receptors may help in clarifying this issue. To this purpose, we generated a mouse model overexpressing S1P receptor type 1 (S1P1) specifically in the myeloid compartment and studied the effect on atherosclerosis development.
Methods
Mice overexpressing S1P1 in myeloid cells (monocytes and macrophages) were generated by crossing mice expressing the murine S1P1 gene under a promoter containing a floxed blocking element with mice expressing Cre recombinase under the control of lysozyme (LysMCre) promoter. Bone marrows from these or control mice were transplanted into low density lipoprotein receptor (LDL-R)-deficient mice and resulting chimeras were fed a Western diet for 14 weeks.
Results
S1P1 overexpressing macrophages showed increased expression and activity of transcription factors PU.1, IRF8 and LXR. This skewed macrophages towards an anti-inflammatory M2 phenotype with enhanced production of IL-10, IL-1RA and IL-5. In addition, S1P1 overexpressing macrophages showed increased ABCA1- and ABCG1-dependent cholesterol efflux, accelerated reversed cholesterol transport, enhanced expression of MerTK and Axl1 and efferocytosis, and reduced endoplasmic stress-induced apoptosis. Atherosclerotic lesion formation in aortic roots and brachiocephalic arteries as well as necrotic core formation were significantly reduced in mice overexpressing S1P1 in myeloid cells.
Conclusions
S1P1 signaling produces a unique anti-inflammatory and anti-atherogenic macrophage phenotype and countervails the development of atherosclerotic lesions in mice.