Sphingosine 1-phosphate receptor 2 signaling suppresses macrophage phagocytosis and impairs host defense against sepsis (INM3P.416)

Abstract

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 macrophage, its role in regulating macrophage response to bacterial infection remains unclear. Methods: Sepsis was induced in wild-type mice treated with S1PR2 antagonist or S1PR2-deficient mice. The antibacterial ability of cell specific S1PR2 was tested in bone marrow reconstitution or macrophage deletion mice. Signaling molecules responsible for S1PR2 mediated phagocytosis were also measured in bone marrow-derived macrophages. Results: Both genetic deletion and pharmaceutical inhibition of S1PR2 significantly limited bacterial burden, reduced lung damage, and improved survival in experimental sepsis. This protection was attributed to the enhanced phagocytic function of S1PR2-deficient macrophages. Absence of S1PR2 in macrophage inhibits RhoA-dependent cell contraction and promotes IQGAP1-Rac1-dependent lamellipodial protrusion, the different signalings of which depends on the extracellular stimulators. 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 a promising therapeutic approach for sepsis.