Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis

Hou, Jinchao; Chen, Qixing; Zhang, Kai; Cheng, Baoli; Xie, Gary; Wu, Xiaoliang; Luo, Cheng; Chen, Limin; Liu, Hong; Zhao, Bing; Dai, Kezhi; Fang, Xiangming

doi:10.1097/aln.0000000000000725

Cited by 42 publications

(43 citation statements)

References 33 publications

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“…S1P receptor-mediated signalling has been described to influence phagocytosis of various pathogens though, albeit with opposing effects. While McQuiston et al report that S1P 2 -mediated S1P-signalling facilitates phagocytosis of antibody-opsonized Cryptococcus neoformans by alveolar macrophages [37], Hou et al elegantly showed that S1P 2 signalling impaired phagocytosis of Escherichia coli in vitro as well as in an animal model [38]. The observed differences are most likely due to different mechanisms/receptors implicated in the receptor-mediated phagocytosis of fungi, gram-negative bacteria, and antibody-opsonized foreign bodies [39].…”

Section: Discussionmentioning

confidence: 99%

Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration

Müller

Bernstorff²,

Heidecke

et al. 2017

BioMed Research International

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Introduction. Macrophages are key players in complex biological processes. In response to environmental signals, macrophages undergo polarization towards a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid that acts via 5 G-protein coupled receptors (S1P1–5) in order to influence a broad spectrum of biological processes. This study assesses S1P receptor expression on macrophages before and after M1 and M2 polarization and performs a comparative analysis of S1P signalling in the two activational states of macrophages. Methods. Bone marrow derived macrophages (BMDM) from C57 BL/6 mice were cultured under either M1- or M2-polarizing conditions. S1P-receptor expression was determined by quantitative RT-PCR. Influence of S1P on macrophage activation, migration, phagocytosis, and cytokine secretion was assessed in vitro. Results. All 5 S1P receptor subclasses were expressed in macrophages. Culture under both M1- and M2-polarizing conditions led to significant downregulation of S1P1. In contrast, M1-polarized macrophages significantly downregulated S1P4. The expression of the remaining three S1P receptors did not change. S1P increased expression of iNOS under M2-polarizing conditions. Furthermore, S1P induced chemotaxis in M1 macrophages and changed cytokine production in M2 macrophages. Phagocytosis was not affected by S1P-signalling. Discussion. The expression of different specific S1P receptor profiles may provide a possibility to selectively influence M1- or M2-polarized macrophages.

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Section: Discussionmentioning

confidence: 99%

Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration

Müller

Bernstorff²,

Heidecke

et al. 2017

BioMed Research International

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“…Thus, S1P 2 reduced antigen capture by murine Langerhans cells, thereby potentially alleviating cutaneous contact hypersensitivity ( Japtok et al, 2012 ). S1P 2 furthermore suppressed macrophage phagocytosis, thereby impairing host defense in sepsis ( Hou et al, 2015 ). Finally, while knockout and blockade of S1P 2 improved the tightness of blood–brain barrier and ameliorated EAE, the receptor was found to be more abundant in female EAE mice and female patients with multiple sclerosis compared to their male counterparts, and it was suggested that this underlies the enhanced female CNS autoimmune susceptibility ( Cruz-Orengo et al, 2014 ).…”

Section: Inflammation and Fibrosismentioning

confidence: 99%

Sphingosine-1-Phosphate Receptor-2 Antagonists: Therapeutic Potential and Potential Risks

et al. 2016

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The sphingosine-1-phosphate (S1P) signaling system with its specific G-protein-coupled S1P receptors, the enzymes of S1P metabolism and the S1P transporters, offers a multitude of promising targets for drug development. Until today, drug development in this area has nearly exclusively focused on (functional) antagonists at the S1P1 receptor, which cause a unique phenotype of immunomodulation. Accordingly, the first-in class S1P1 receptor modulator, fingolimod, has been approved for the treatment of relapsing-remitting multiple sclerosis, and novel S1P1 receptor (functional) antagonists are being developed for autoimmune and inflammatory diseases such as psoriasis, inflammatory bowel disease, lupus erythematodes, or polymyositis. Besides the S1P1 receptor, also S1P2 and S1P3 are widely expressed and regulate many diverse functions throughout the body. The S1P2 receptor, in particular, often exerts cellular functions which are opposed to the functions of the S1P1 receptor. As a consequence, antagonists at the S1P2 receptor have the potential to be useful in a contrasting context and different areas of indication compared to S1P1 antagonists. The present review will focus on the therapeutic potential of S1P2 receptor antagonists and discuss their opportunities as well as their potential risks. Open questions and areas which require further investigations will be emphasized in particular.

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“…Another cellular messenger, S1PR2, is the most important receptor for S1P in macrophages and was positively correlated with the severity of sepsis [ 34 – 35 ]. S1PR2 has been reported to induce NF-κB activation by promoting the phosphorylation of PI3K/Akt [ 36 – 37 ].…”

Section: Discussionmentioning

confidence: 99%

Changes of Foxo3a in PBMCs and its associations with stress hyperglycemia in acute obstructive suppurative cholangitis patients

Niu

Chen

et al. 2017

Oncotarget

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ObjectiveThe levels of Foxo3a in the peripheral blood mononuclears cells (PBMCs) before and after treatment were detected in acute obstructive suppurative cholangitis (AOSC) patients to evaluate the associations between Foxo3a and stress hyperglycemia (SHG).MethodsPBMCs were obtained from AOSC patients (n=28) on admission (AP), from patients at 1 week after cure (RP) and from healthy volunteers (HV) (n=14) to evaluate the relationship between the protein levels of Foxo3a and the serum levels of glucose. Signaling pathways, which link inflammation and glycometabolism, simultaneously affecting the expression of Foxo3a, were detected. In addition, cytokines were detected in PBMCs and AOSC mouse models, which were pre-treated with Foxo3a agonist.ResultsThe levels of glucose and p-Foxo3a in the AP were significantly higher than those in the RP and HV, where as the levels of Foxo3a in the AP were lower than those in the RP and HV. Foxo3a levels in the AP normalized against RP were strongly negatively correlated with the glucose levels in the AP normalized against RP. The levels of sphingosine-1-phosphate receptor 2 (S1PR2) in the AP were higher than those in the RP and HV. In addition, inhibition of Foxo3a phosphorylation, coupled with the down-regulation of S1PR2, attenuated the LPS-induced inflammatory response in the PBMCs and AOSC mouse models.ConclusionsFoxo3a is correlated with the dysregulation of glucose homeostasis in the pathogenesis of AOSC-induced sepsis by inhibiting the activation of PI3K/Akt-S1PR2 and NF-κB pathways, hinting at a switched role and therapeutic potentialities in the early stage of sepsis.

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Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis

Abstract: This study implies that S1PR2, as a critical receptor in macrophage, impairs phagocytosis and antimicrobial defense in the pathogenesis of sepsis. Interventions targeting S1PR2 signaling may serve as promising therapeutic approaches for sepsis.

Cited by 42 publications

References 33 publications

Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration

Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration

Sphingosine-1-Phosphate Receptor-2 Antagonists: Therapeutic Potential and Potential Risks

Changes of Foxo3a in PBMCs and its associations with stress hyperglycemia in acute obstructive suppurative cholangitis patients

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