1 Department of Anesthesiology and Intensive Care, The First Affiliated Hospital.
2 The Children's Hospital, and.
Am J Respir Crit Care Med. 2017 Dec 15;196(12):1559-1570. doi: 10.1164/rccm.201701-0241OC.
Efficient elimination of 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.
To investigate the role of S1PR3 in antibacterial immunity during sepsis.
Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers.
S1PR3 protein levels were up-regulated in macrophages upon bacterial stimulation. 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. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates 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 vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes.
S1PR3 signaling drives bacterial 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.
有效清除致病菌是脓毒症结局的关键决定因素。在脓毒症中，鞘氨醇-1-磷酸受体 3（S1PR3）介导炎症反应的多个方面，但 S1PR3 信号是否对消除入侵病原体是必需的尚不清楚。
研究 S1PR3 在脓毒症期间抗菌免疫中的作用。
使用细胞和鼠模型进行了缺失和功能获得实验。测定了脓毒症患者和健康志愿者的 S1PR3 水平。
细菌刺激后巨噬细胞中 S1PR3 蛋白水平上调。S1pr3 小鼠在多种脓毒症模型中死亡率增加，细菌负荷增加。野生型骨髓来源巨噬细胞的转移使 S1pr3 小鼠免于致命性脓毒症。S1PR3 过表达的巨噬细胞进一步降低了脓毒症的死亡率。S1PR3 的缺失导致巨噬细胞中细菌杀伤明显减少。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，并提高多种脓毒症模型的存活率。在机制上，由于吞噬体中 vacuolar protein-sorting 34 的募集受损，S1pr3 巨噬细胞中的活性氧水平降低，吞噬体成熟延迟。此外，脓毒症患者单核细胞中的 S1RP3 表达水平升高。单核细胞 S1PR3 水平升高与有效的细胞内杀菌活性、更好的免疫状态和更好的预后相关。
S1PR3 信号驱动细菌杀伤，是细菌性脓毒症生存的必要条件。针对 S1PR3 信号的干预可能对操纵先天免疫反应以对抗病原体具有转化意义。
