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Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation.

ABSTRACT: Macrophage recruitment to sites of inflammation is an essential step in host defense. However, the mechanisms preventing excessive accumulation of macrophages remain relatively unknown. The lysophospholipid sphingosine 1-phosphate (S1P) promotes T and B cell egress from lymphoid organs by acting on S1P receptor 1 (S1P(1)R). More recently, S1P(5)R was shown to regulate NK cell mobilization during inflammation, raising the possibility that S1P regulates the trafficking of other leukocyte lineages. In this study, we show that S1P(2)R inhibits macrophage migration in vitro and that S1P(2)R-deficient mice have enhanced macrophage recruitment during thioglycollate peritonitis. We identify the signaling mechanisms used by S1P(2)R in macrophages, involving the second messenger cAMP and inhibition of Akt phosphorylation. In addition, we show that the phosphoinositide phosphatase and tensin homolog deleted on chromosome 10, which has been suggested to mediate S1P(2)R effects in other cell types, does not mediate S1P(2)R inhibition in macrophages. Our results suggest that S1P serves as a negative regulator of macrophage recruitment by inhibiting migration in these cells and identify an additional facet to the regulation of leukocyte trafficking by S1P.

SUBMITTER: Michaud J

PROVIDER: S-EPMC3068864 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation.

Michaud Jason J Im Dong-Soon DS Hla Timothy T

Journal of immunology (Baltimore, Md. : 1950) 20091230 3

Macrophage recruitment to sites of inflammation is an essential step in host defense. However, the mechanisms preventing excessive accumulation of macrophages remain relatively unknown. The lysophospholipid sphingosine 1-phosphate (S1P) promotes T and B cell egress from lymphoid organs by acting on S1P receptor 1 (S1P(1)R). More recently, S1P(5)R was shown to regulate NK cell mobilization during inflammation, raising the possibility that S1P regulates the trafficking of other leukocyte lineages. ...[more]

PMID: 20042570

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Project description:NLR family pyrin domain containing 3 (NLRP3) inflammasome accompanies chronic liver injury and is a critical mediator of inflammation-driven liver fibrosis. Sphingosine 1-phosphate (S1P)/S1P Receptor (S1PR) signaling participates in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophage (BMM) activation. However, the relationship between S1P/S1PR signaling and NLRP3 inflammasome in BMMs remains unclear. Here, we found significantly elevated gene expression of NLRP3 inflammasome components (NLRP3, pro-interleukin-1β, and pro-interleukin-18) and the activation of NLRP3 inflammasome significantly elevated during murine chronic liver injury induced by a bile duct ligation operation, a methionine-choline-deficient and high-fat diet, or carbon tetrachloride intraperitoneal injection. Moreover, the increased expression of sphingosine kinase 1 (SphK1), the rate-limiting synthetic enzyme of S1P, was positively correlated with NLRP3 inflammasome components in both patients and mouse model livers. Flow cytometry analysis and immunofluorescence staining showed BMMs contributed to the significant proportion of NLRP3+ cells in murine inflammatory livers, but not Kupffer cells, dendritic cells, endothelial cells, T cells, and hepatocytes. Focusing on macrophages, S1P promoted NLRP3 inflammasome priming and activation in a dose-dependent manner. Blockade of S1PR2 by JTE-013 (antagonist of S1PR2) or S1PR2-siRNA inhibited S1P-induced NLRP3 inflammasome priming and inflammatory cytokine (interleukin-1β and interleukin-18) secretion, whereas blockade of S1PR1 or S1PR3 had no such effect. in vivo, a β1,3-d-glucan-encapsulated siRNA particle (GeRP) delivery system is capable of silencing genes in macrophages specifically. Treatment with S1PR2 siRNA-GeRPs markedly reduced NLRP3 inflammasome priming and activation and attenuated liver inflammation and fibrosis. Together, the conclusions indicated that targeting macrophage S1PR2 retarded liver inflammation and fibrogenesis via downregulating NLRP3 inflammasome, which may represent an effective therapeutic strategy for chronic liver injury.

Project description:Lymphatic endothelial cell homeostasis plays important roles in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodeling after myocardial infarction (MI). Our results revealed that sphingosine 1-phosphate receptor 1 (S1pr1) expression in cardiac lymphatic endothelial cells (LECs) was sharply changed after MI. It has been shown that S1pr1 tightly controlled LEC functions and homeostasis. We thus hypothesized that lymphatic endothelial S1pr1 might be involved in post-MI cardiac remodeling. We generated LEC-conditional S1pr1 transgenic mice, in which S1pr1 expression was reduced in cardiac LECs. We performed the left anterior descending coronary artery (LAD) ligation operation to induce MI in these mice. Cardiac functions and remodeling were examined by echocardiography analysis and serial histological analysis. Meanwhile, we performed adoptive cell transfer experiments to monitor macrophage trafficking in post-MI myocardium and their draining lymphatic system. Furthermore, in vitro cell culture experiments and mechanism studies were undertaken to uncover the molecular mechanism by which LEC-S1pr1 regulated cardiac inflammation and remodeling after MI. Our results showed that S1pr1 expression significantly decreased in cardiac LECs after MI. Our in vivo experiments showed that the reduced expression of LEC-S1pr1 deteriorated cardiac function and worsened pathological cardiac remodeling after MI. Our further results demonstrated that the reduced expression of LEC-S1pr1 did not influence macrophage infiltration in an early inflammatory phase of MI, but significantly affected macrophages clearance in the later phase of MI via afferent cardiac lymphatics, and thus influenced inflammatory responses and cardiac outcome after MI. Further study showed that S1P/S1pr1 activated ERK signaling pathway and enhanced CCL2 expression, which promoted macrophage trafficking in a paracrine manner. This study reveals that cardiac lymphatic endothelial cells tightly control macrophage trafficking via lymphatic vessels in injured hearts via S1P/S1pr1/ERK/CCL2 pathway and thus regulate post-MI immune modulation and heart repair. This study highlights the importance of cardiac lymphatic vessel system in orchestrating post-MI immune responses and cardiac remodeling by regulating macrophage transit in injured hearts. Our finding implies that a feasible modulation of S1pr1 signaling in LECs might provide a promising target to resolve excessive inflammation and to ameliorate adverse cardiac remodeling after MI.

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Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation.

Publications

Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation.

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