Critical Care Medicine  |   August 2018
Sphingosine-1-phosphate Receptor 2 Signaling Promotes Caspase-11–dependent Macrophage Pyroptosis and Worsens Escherichia coli Sepsis Outcome
Author Notes
  • From the Department of Anesthesiology and Intensive Care Unit, the First Affiliated Hospital (F.S., J.H., Z.C., B.C., R.L., P.C., Y.S., X.F.); and Department of Anesthesiology and Intensive Care Unit, Sir Run Run Shaw Hospital (H.W.), School of Medicine, Zhejiang University, Hangzhou, China.
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • Corresponding article on page 238.
    Corresponding article on page 238.×
  • 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).×
  • F.S. and J.H. contributed equally to this article.
    F.S. and J.H. contributed equally to this article.×
  • Submitted for publication August 4, 2017. Accepted for publication February 22, 2018.
    Submitted for publication August 4, 2017. Accepted for publication February 22, 2018.×
  • Address correspondence to Dr. Fang: Department of Anesthesiology and Intensive Care Unit, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China. 0099418@zju.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 / Basic Science / Critical Care / Infectious Disease
Critical Care Medicine   |   August 2018
Sphingosine-1-phosphate Receptor 2 Signaling Promotes Caspase-11–dependent Macrophage Pyroptosis and Worsens Escherichia coli Sepsis Outcome
Anesthesiology 8 2018, Vol.129, 311-320. doi:10.1097/ALN.0000000000002196
Anesthesiology 8 2018, Vol.129, 311-320. doi:10.1097/ALN.0000000000002196
Abstract

What We Already Know about This Topic:

  • No molecular-targeted treatments for sepsis have proved successful in humans. The role of sphingosine-1-phosphate receptor 2 (S1PR2) signaling in sepsis is uncertain.

What This Article Tells Us That Is New:

  • In an in vivo mouse model of Gram-negative sepsis, deletion of the gene for sphingosine-1-phosphate receptor 2 (S1PR2) reduced pyroptosis, possibly by decreased activation of caspase-11, and increased survival. S1PR2 and caspase-11 may be testable targets in sepsis.

Background: Pyroptosis, a type of proinflammatory programmed cell death, drives cytokine storm. Caspase-11–dependent macrophage pyroptosis contributes to mortality during sepsis. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling can amplify interleukin-1β secretion in endotoxin-induced inflammation. Here, we hypothesized that S1PR2 signaling increases caspase-11–dependent macrophage pyroptosis and worsens Gram-negative sepsis outcome.

Methods: A Gram-negative sepsis model was induced through intraperitoneal injection of Escherichia coli. Primary peritoneal macrophages isolated from wild-type, S1pr2-deficient (S1pr2-/-), or nucleotide-binding oligomerization domain-like receptor protein-3–deficient mice were treated with E. coli. Caspase-11 activation, macrophage pyroptosis, and Ras homolog gene family, member A-guanosine triphosphate levels were assessed in those cells. Additionally, monocyte caspase-4 (an analog of caspase-11) expression and its correlation with S1PR2 expression were determined in patients with Gram-negative sepsis (n = 11).

Results: Genetic deficiency of S1PR2 significantly improved survival rate (2/10 [20%] in wild-type vs. 7/10 [70%] in S1pr2-/-, P = 0.004) and decreased peritoneal macrophage pyroptosis (pyroptosis rate: 35 ± 3% in wild-type vs. 10 ± 3% in S1pr2-/-, P < 0.001). Decreased caspase-11 activation in S1PR2 deficiency cells contributed to the reduced macrophage pyroptosis. In addition, RhoA inhibitor abrogated the amplified caspase-11 activation in wild-type or S1PR2-overexpressing cells. In patients with Gram-negative sepsis, caspase-4 increased significantly in monocytes compared to nonseptic controls and was positively correlated with S1PR2 (r = 0.636, P = 0.035).

Conclusions: S1PR2 deficiency decreased macrophage pyroptosis and improved survival in E. coli sepsis. These beneficial effects were attributed to the decreased caspase-11 activation of S1PR2-deficient macrophages. S1PR2 and caspase-11 may be promising new targets for treatment of sepsis.