Newly Published
Critical Care Medicine  |   February 2020
Inhibition of Sphingosine Kinase 1 Attenuates Sepsis-induced Microvascular Leakage via Inhibiting Macrophage NLRP3 Inflammasome Activation in Mice
Author Notes
  • From the Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • M.Z. and W.W. contributed equally to this article.
    M.Z. and W.W. contributed equally to this article.×
  • Submitted for publication November 20, 2018. Accepted for publication January 2, 2020.
    Submitted for publication November 20, 2018. Accepted for publication January 2, 2020.×
  • Correspondence: Address correspondence to Dr. Zhu: Department of Critical Care Medicine, Zhongshan Hospital Fudan University, 180 Fenglin Road, Shanghai, China. zhuduming@fudan.edu.cn. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Gastrointestinal and Hepatic Systems / Infectious Disease / Respiratory System
Critical Care Medicine   |   February 2020
Inhibition of Sphingosine Kinase 1 Attenuates Sepsis-induced Microvascular Leakage via Inhibiting Macrophage NLRP3 Inflammasome Activation in Mice
Anesthesiology Newly Published on February 27, 2020. doi:https://doi.org/10.1097/ALN.0000000000003192
Anesthesiology Newly Published on February 27, 2020. doi:https://doi.org/10.1097/ALN.0000000000003192
Abstract

Background: Sepsis is the overwhelming inflammatory response to infection, in which nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role. Shingosine-1-phosphate is reported to evoke NLRP3 inflammasome activation. Sphingosine kinase 1 (SphK1) is the major kinase that catalyzes bioactive lipid shingosine-1–phosphate formation and its role in sepsis remains uncertain. The authors hypothesize that SphK1 elicits NLRP3 inflammasome activation and exacerbates sepsis.

Methods: Peripheral blood mononuclear cells were isolated from septic patients and healthy volunteers to measure messenger RNA (mRNA) expression. In mice, sepsis was induced by cecal ligation and puncture. Bone marrow–derived macrophages were prepared from C57BL/6J wild-type, Casp1−/−, Nlrp3−/− and SphK1−/− mice. PF-543 was used as the specific inhibitor of SphK1. Mortality, peripheral perfusion, lung Evan’s blue dye index, lung wet/dry ratio, lung injury score, lung myeloperoxidase activity, NLRP3 activation, and function of endothelial adherens junction were measured.

Results: SphK1 mRNA expression was higher in cells from septic patients versus healthy volunteers (septic patients vs. healthy volunteers: 50.9 ± 57.0 fold change vs. 1.2 ± 0.1 fold change, P < 0.0001) and was positively correlated with IL-1β mRNA expression in these cells (r = 0.537, P = 0.012) and negatively correlated with PaO2/Fio2 ratios (r = 0.516, P = 0.017). In mice that had undergone cecal ligation and puncture, the 5-day mortality was 30% in PF-543–treated group and 80% in control group (n = 10 per group, P = 0.028). Compared with controls, PF-543–treated mice demonstrated improved peripheral perfusion and alleviated extravascular Evan’s blue dye effusion (control vs. PF-543: 25.5 ± 3.2 ng/g vs. 18.2 ± 1.4 ng/g, P < 0.001), lower lung wet/dry ratio (control vs. PF-543: 8.0 ± 0.2 vs. 7.1 ± 0.4, P < 0.0001), descending lung injury score, and weaker lung myeloperoxidase activity. Inhibition of SphK1 suppressed caspase-1 maturation and interleukin-1β release through repressing NLRP3 inflammasome activation, and subsequently stabilized vascular endothelial cadherin through suppressing interleukin-1β–evoked Src-mediated phosphorylation of vascular endothelial cadherin.

Conclusions: SphK1 plays a crucial role in NLRP3 inflammasome activation and contributes to lung injury and mortality in mice polymicrobial sepsis.

Editor’s Perspective:

What We Already Know about This Topic:

  • Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasomes are intracellular multiprotein complexes in innate immune cells that may be activated in sepsis

  • Sphingosine-1-phosphate is a biolipid that has been suggested to be involved in NLRP3 activation, but its role in sepsis and NLRP3 inflammasome activation is not understood

  • Sphingosine kinase 1 mediates sphingosine-1-phosphate formation

What This Article Tells Us That Is New:

  • In peripheral blood mononuclear cells from septic patients, lipopolysaccharide-stimulated sphingosine-1-phosphate messenger RNA expression was higher than in cells from healthy volunteers

  • In male mouse model of sepsis, treatment with a specific inhibitor of sphingosine kinase 1 decreased mortality, improved peripheral perfusion, and diminished capillary leak

  • Results suggest that sphingosine kinase 1 may participate in NLRP3 activation, and septic lung injury and mortality in mice