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

Abstract

BACKGROUND:

Sepsis is characterized by an inappropriate systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Sphingosine 1-phosphate receptor 2 (S1PR2) modulates endotoxin-induced inflammation in endothelium. However, as a highly expressed S1P receptor in macrophages, its role in regulating macrophage response to bacterial infection remains unclear.

METHODS:

Cecal ligation and puncture or intratracheal instillation of Escherichia coli was induced in wild-type or S1pr2-deficient mice. The antibacterial ability of cell-specific S1PR2 was tested in bone marrow reconstitution mice or mice with macrophage-specific deletion. Signaling molecules responsible for S1PR2-mediated phagocytosis were also measured in the bone marrow-derived macrophages. In addition, S1PR2 expression levels and its correlation with severity of sepsis were determined in critically ill patients (n = 25).

RESULTS:

Both genetic deletion and pharmaceutical inhibition of S1PR2 significantly limited bacterial burden, reduced lung damage, and improved survival (genetic deletion, 0% in S1pr2 vs. 78.6% in S1pr2, P < 0.001; pharmaceutical inhibition, 9.1% in vehicle vs. 22.2% in S1PR2 antagonist, P < 0.05). This protection was attributed to the enhanced phagocytic function of S1PR2-deficient macrophages (mean fluorescent intensity, 2035.2 ± 202.1 vs. 407.8 ± 71.6, P < 0.001). Absence of S1PR2 in macrophage inhibits RhoA-dependent cell contraction and promotes IQGAP1-Rac1-dependent lamellipodial protrusion, whose signaling pathways depend on extracellular stimulators. In septic patients, increased S1PR2 levels in peripheral blood mononuclear cells were positively correlated with the severity of sepsis (r = 0.845, P < 0.001).

CONCLUSIONS:

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.

• Authors: JinChao Hou, QiXing Chen, Kai Zhang, BaoLi Cheng, GuoHao Xie, XiaoLiang Wu, Cheng Luo, LiMin Chen, Hong Liu, Bing Zhao, KeZhi Dai, XiangMing Fang
• Journal: Anesthesiology (Anesthesiology) Vol. 123 Issue 2 Pg. 409-22 (Aug 2015) ISSN: 1528-1175 [Electronic] United States
• PMID: 26200183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Lysosphingolipid
• Sphingosine-1-Phosphate Receptors
• sphingosine-1-phosphate receptor-2, mouse

Topics

• Animals
• Cells, Cultured
• Female
• Host Specificity (physiology)
• Macrophages (immunology, metabolism)
• Male
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Phagocytosis (physiology)
• Receptors, Lysosphingolipid (deficiency)
• Sepsis (immunology, metabolism)
• Signal Transduction (physiology)
• Sphingosine-1-Phosphate Receptors