title: 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.affiliation: From the Department of Anesthesiology and Intensive Care Unit, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (J.H., Q.C., K.Z., B.C., G.X., X.W., B.Z., K.D., X.F.); and Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (C.L., L.C., H.L.).
authors.forename: JinChao
authors.initials: J
authors.lastname: Hou
authors.forename: QiXing
authors.initials: Q
authors.lastname: Chen
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: BaoLi
authors.initials: B
authors.lastname: Cheng
authors.forename: GuoHao
authors.initials: G
authors.lastname: Xie
authors.forename: XiaoLiang
authors.initials: X
authors.lastname: Wu
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: LiMin
authors.initials: L
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Zhao
authors.forename: KeZhi
authors.initials: K
authors.lastname: Dai
authors.forename: XiangMing
authors.initials: X
authors.lastname: Fang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D058507:Host Specificity / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000172:deficiency*; D018805:Sepsis / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse