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

doi:10.1097/ALN.0000000000000725

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	Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis
	Hou, JinChao 1,2; Chen, QiXing 1,2; Zhang, Kai 1,2; Cheng, BaoLi 1,2; Xie, GuoHao 1,2; Wu, XiaoLiang 1,2; Luo, Cheng3 ; Chen, LiMin 3; Liu, Hong3 ; Zhao, Bing 1,2
刊名	ANESTHESIOLOGY
	2015-08
卷号	123 期号:2 页码:409-422
ISSN号	0003-3022
DOI	10.1097/ALN.0000000000000725
文献子类	Article
英文摘要	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, 2035.2202.1 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.
资助项目	National Natural Science Foundation of China, Beijing, China[81130036] ; National Natural Science Foundation of China, Beijing, China[81201495] ; National Natural Science Foundation of China, Beijing, China[81102226] ; National Natural Science Foundation of China, Beijing, China[91229204] ; Specialized Research Fund for the Doctoral Program of Higher Education of China, Beijing, China[20130101120029] ; National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, Beijing, China[2012BAI11B05]
WOS关键词	ENHANCING BACTERIAL CLEARANCE ; POLYMICROBIAL SEPSIS ; SPHINGOSINE-1-PHOSPHATE ; INFLAMMATION ; RAC ; PATHOGENESIS ; SPECIFICITY ; SELECTIVITY ; ACTIVATION ; PROTECTS
WOS研究方向	Anesthesiology
语种	英语
出版者	LIPPINCOTT WILLIAMS & WILKINS
WOS记录号	WOS:000363537300018
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276443]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Fang, XiangMing
作者单位	1.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Intens Care Unit, Hangzhou 310003, Zhejiang, Peoples R China; 2.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Dept Anesthesiol, Hangzhou 310003, Zhejiang, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Hou, JinChao,Chen, QiXing,Zhang, Kai,et al. Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis[J]. ANESTHESIOLOGY,2015,123(2):409-422.
APA	Hou, JinChao.,Chen, QiXing.,Zhang, Kai.,Cheng, BaoLi.,Xie, GuoHao.,...&Fang, XiangMing.(2015).Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis.ANESTHESIOLOGY,123(2),409-422.
MLA	Hou, JinChao,et al."Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis".ANESTHESIOLOGY 123.2(2015):409-422.