Increased Susceptibility of S1PR3-Deficient Mice to Escherichia coli Sepsis Is Associated with an Impaired Bactericidal Activity in Macrophage

Abstract

Abstract Background Sepsis, a leading cause of death in critically ill patients worldwide, is characterized with imbalanced proinflammatory responses and compromised bacterial clearance in host immunity. Monocytes/macrophages play a crucial role in elimination of bacteria through innate immunity receptors. Methods We explored the effect of Sphingosine-1-phosphate receptor 3 (S1PR3) gene deficiency on mortality, organ injury, and bacterial clearance in cecal ligation and puncture (CLP) or Escherichia coli (E. coli)-induced sepsis. Signaling molecules responsible for S1PR3-mediated bactericidal function were dissected in peritoneal macrophages. Furthermore, S1PR3 specific agonist (GPS-725.017) was evaluated for treatment of sepsis. Results After sepsis onset, S1pr3−/− mice showed increased mortality and organ injury, which attributed to markedly decreased E. coli killing. Mechanically, S1PR3 regulated activity of the NADPH oxidase NOX2 complex and phagolysosomal maturation through recruiting the intracellular class III phosphatidylinositol kinase Vps34 to the phagosome. S1PR3 specific agonist (GPS-725.017) enhanced NOX2 activity in E. coli-containing phagosomes and bactericidal function in wild-type macrophages. Additionally, the survival of mice treated with GPS-725.017 was improved when compared with those treated with vehicle. Conclusion S1PR3 is an important receptor to connect bacterial phagosome to ubiquitous cellular machinery responsible for control of bacterial killing in macrophage. Interventions targeting S1PR3 signaling may serve as promising therapeutic approaches for sepsis.