Rationale: Efficiently eliminating pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. Objectives: To investigate the role of S1PR3 in antibacterial immunity during sepsis. Methods: Loss and gain of function experiments were performed using cell and murine models. S1PR3 levels were determined in septic patients and healthy volunteers. Measurements and Main Results: S1PR3 protein levels were upregulated in macrophages upon bacterial stimuli. S1pr3-/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3-/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. The loss of S1PR3 led to markedly decreased bactericidal killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated macrophage bactericidal function and improved the survival in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3-/- macrophages due to impaired recruitment of the vacuolar protein sorting 34 to the phagosomes. In addition, the S1RP3 expression levels were elevated in monocytes from septic patients. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status and preferable outcomes. Conclusions: S1PR3 signaling drives bactericidal killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.

中文翻译：

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S1PR3信号驱动杀菌杀伤，对于细菌性败血症的存活是必需的

理由：有效消除病原细菌是败血症结果的关键决定因素。鞘氨醇-1-磷酸受体3（S1PR3）介导败血症过程中炎症反应的多个方面，但是S1PR3信号是否对于消除入侵的病原体是否必要仍是未知的。目的：探讨脓毒症中S1PR3在抗菌免疫中的作用。方法：使用细胞和鼠模型进行功能丧失和获得实验。在败血病患者和健康志愿者中确定S1PR3水平。测量和主要结果：细菌刺激后，巨噬细胞中的S1PR3蛋白水平上调。S1pr3-/-小鼠在多种败血症模型中显示出更高的死亡率和细菌负荷。野生型骨髓巨噬细胞的转移从致命性败血症中拯救了S1pr3-/-小鼠。S1PR3过表达的巨噬细胞进一步改善了败血症的死亡率。S1PR3的丢失导致巨噬细胞中杀菌作用的明显降低。使用肽激动剂增强内源性S1PR3活性可增强巨噬细胞的杀菌功能，并提高了败血症多种模型的存活率。机械上，S1pr3-/-巨噬细胞中的活性氧水平降低，吞噬体的成熟被延迟，这是由于液泡蛋白分选34募集到吞噬体的能力受损。此外，脓毒症患者单核细胞中S1RP3的表达水平升高。高水平的单核细胞S1PR3与有效的细胞内杀菌活性相关，更好的免疫状态和更好的结果。结论：S1PR3信号驱动杀菌作用，并且对于细菌性败血症的存活至关重要。靶向S1PR3信号的干预可能对操纵与病原体战斗的先天免疫应答具有翻译意义。