S1PR3 Signaling Drives Bacterial Killing and Is Required for Survival in Bacterial Sepsis

Am J Respir Crit Care Med. 2017 Dec 15;196(12):1559-1570. doi: 10.1164/rccm.201701-0241OC.

Abstract

Rationale: 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.

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 patients with sepsis and healthy volunteers.

Measurements and main results: 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.

Conclusions: 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.

Keywords: S1PR3; bacterial clearance; intervention; macrophage; sepsis.

MeSH terms

  • Animals
  • Cell Death / genetics
  • Cell Death / immunology*
  • Disease Models, Animal
  • Disease-Free Survival
  • Humans
  • Mice
  • Receptors, Lysosphingolipid / genetics*
  • Receptors, Lysosphingolipid / immunology*
  • Sepsis / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Sphingosine-1-Phosphate Receptors
  • Up-Regulation / genetics
  • Up-Regulation / immunology

Substances

  • Receptors, Lysosphingolipid
  • S1pr3 protein, mouse
  • Sphingosine-1-Phosphate Receptors
  • sphingosine-1-phosphate receptor-3, human