Sphingosine-1-Phosphate Receptor 3 Promotes Recruitment of Monocyte/Macrophages in Inflammation and Atherosclerosis

Abstract

Rationale:The role of sphingosine-1-phosphate (S1P) and its receptors in the pathogenesis of atherosclerosis has not been investigated. Objective:We hypothesized that the S1P receptor 3 (S1P 3 ) plays a causal role in the pathogenesis of atherosclerosis. Methods and Results:We examined atherosclerotic lesion development in mice deficient for S1P 3 and apolipoprotein (Apo)E. Although S1P 3 deficiency did not affect lesion size after 25 or 45 weeks of normal chow diet, it resulted in a dramatic reduction of the monocyte/macrophage content in lesions of S1P 3 ؊/؊ /ApoE ؊/؊ double knockout mice. To search for putative defects in monocyte/macrophage recruitment, we examined macrophagedriven inflammation during thioglycollate-induced peritonitis. Elicited peritoneal macrophages were reduced in S1P 3 -deficient mice and expressed lower levels of tumor necrosis factor-␣ and monocyte chemoattractant protein-1. Bone marrow-derived S1P 3 -deficient macrophages produced less MCP-1 in response to lipopolysaccharide stimulation. In vitro, S1P was chemotactic for wild-type but not S1P 3 -deficient peritoneal macrophages. In vivo, S1P concentration increased rapidly in the peritoneal cavity after initiation of peritonitis. Treatment with the S1P analog FTY720 attenuated macrophage recruitment to the peritoneum. Studies in bone marrow chimeras showed that S1P 3 in both hematopoietic and nonhematopoietic cells contributed to monocyte/macrophage accumulation in atherosclerotic lesions. Finally, S1P 3 deficiency increased the smooth muscle cell content of atherosclerotic lesions and enhanced neointima formation after carotid ligation arguing for an antiproliferative/antimigratory role of S1P 3 in the arterial injury response. Conclusions:Our data suggest that S1P 3 mediates the chemotactic effect of S1P in macrophages in vitro and in vivo and plays a causal role in atherosclerosis by promoting inflammatory monocyte/macrophage recruitment and altering smooth muscle cell behavior. (Circ Res. 2011;108:314-323.)Key Words: sphingosine-1-phosphate (S1P) Ⅲ atherosclerosis Ⅲ macrophages Ⅲ inflammation Ⅲ vascular biology Ⅲ lipid metabolites S phingosine-1-phosphate (S1P) is a bioactive lipid with key functions in the immune, inflammatory, and cardiovascular systems. S1P is abundant in plasma (200 to 1000 nmol/L 1,2 ), where it is contained mainly in the high-density lipoprotein fraction 3 in a biologically active form. 4 Accordingly, plasma S1P levels correlate positively with plasma high-density lipoprotein cholesterol and apolipoprotein AI. 2 As a component of both plasma and interstitial fluid, S1P interacts with all vascular and nonvascular cell types that participate in the pathogenesis of atherosclerosis. All these cells have functional S1P receptors and respond to S1P in a number of different ways, 5 which has prompted the question whether S1P and its receptors may play a role in the pathogenesis of atherosclerosis. A positive association between serum S1P levels and the severity of coronary artery stenosis has been described in ...

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

“…Strikingly, at flow rates similar to physiological (2-5 dynes/cm 2 ), mononuclear cell adhesion to endothelial cells pretreated with LPS plus S1P showed a similar resistance to shear stress than cells pretreated with TNF-a, although the number of cells attached was not as high as with TNF-a, which argues for a minimal threshold of adhesion molecules required for a strong cell adhesion. These observations are consistent with earlier reports showing that exposure to S1P increases surface expression of adhesion molecules in endothelial cells (9,28) and that the S1P-S1P 3 axis promotes leukocyte recruitment in inflammation and atherosclerosis (29). However, our results differ from studies in which S1P prevents TNF-a-mediated monocyte adhesion to aortic endothelium in mice (30), and S1P protects ischemiareperfusion via S1P 3 by suppressing leukocyte adhesion (31).…”

“…Moreover, S1P 3 has been pinpointed as the receptor involved in proadhesive S1P effects, while S1P 1 would account for its anti-adhesive properties in in vitro studies, suggesting S1P receptor subtype specificity (36). Furthermore, the role of S1P 3 in atherogenesis has recently been emphasized by a report demonstrating that S1P 3 promotes recruitment of monocytes/macrophages in inflammation and atherosclerosis (29).…”

Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis

“…4). Keul et al showed that the recruitment of monocytes that contributed to atherosclerosis was dependent on S1P 3 (30). Because S1P 3 acts as a modulator of SDF-1-mediated chemotaxis, differential expression is likely responsible for the differences in SDF-1α-mediated chemotaxis between the two subtypes.…”

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

“…45 An S1P 1 -selective agonist may act directly on macrophage proliferation and trafficking. [26][27][28][29]46 An in vivo proliferation assay demonstrated that CYM did not affect macrophage proliferation. Increasing amounts of data have indicated that the lower number of macrophages in the inflamed tissues of FTY720-treated mice could be an indirect effect of vascular permeability and monocyte recruitment.…”

“…S1P might also be involved in macrophage trafficking. 3,[26][27][28][29] FTY720 reduces macrophage infiltration into sites of inflammation in many inflammatory disease models. [30][31][32][33] The mechanism of action of FTY720 may involve its effects on endothelial cells to reduce monocyte migration.…”