S1P lyase inhibition protects against sepsis by promoting disease tolerance via the S1P/S1PR3 axis
Cynthia Weigel,
Sören S. Hüttner,
Kristin Ludwig,
Nadine Krieg,
Susann Hofmann,
Nathalie H. Schröder,
Linda Robbe,
Stefan Kluge,
Axel Nierhaus,
Martin S. Winkler,
Ignacio Rubio,
Julia von Maltzahn,
Sarah Spiegel,
Markus H. Gräler
Affiliations
Cynthia Weigel
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany
Sören S. Hüttner
Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany
Kristin Ludwig
Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany; Institute of Molecular Cell Biology, Jena University Hospital, 07745 Jena, Germany
Nadine Krieg
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany
Susann Hofmann
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07740 Jena, Germany
Nathalie H. Schröder
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany
Linda Robbe
Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Stefan Kluge
Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Axel Nierhaus
Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Martin S. Winkler
Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, 37075 Göttingen, Germany
Ignacio Rubio
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07740 Jena, Germany
Julia von Maltzahn
Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany
Sarah Spiegel
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
Markus H. Gräler
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07740 Jena, Germany; Corresponding author at: Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.
Background: One-third of all deaths in hospitals are caused by sepsis. Despite its demonstrated prevalence and high case fatality rate, antibiotics remain the only target-oriented treatment option currently available. Starting from results showing that low-dose anthracyclines protect against sepsis in mice, we sought to find new causative treatment options to improve sepsis outcomes. Methods: Sepsis was induced in mice, and different treatment options were evaluated regarding cytokine and biomarker expression, lung epithelial cell permeability, autophagy induction, and survival benefit. Results were validated in cell culture experiments and correlated with patient samples. Findings: Effective low-dose epirubicin treatment resulted in substantial downregulation of the sphingosine 1-phosphate (S1P) degrading enzyme S1P lyase (SPL). Consequent accumulation and secretion of S1P in lung parenchyma cells stimulated the S1P-receptor type 3 (S1PR3) and mitogen-activated protein kinases p38 and ERK, reducing tissue damage via increased disease tolerance. The protective effects of SPL inhibition were absent in S1PR3 deficient mice. Sepsis patients showed increased expression of SPL, stable expression of S1PR3, and increased levels of mucin-1 and surfactant protein D as indicators of lung damage. Interpretation: Our work highlights a tissue-protective effect of SPL inhibition in sepsis due to activation of the S1P/S1PR3 axis and implies that SPL inhibitors and S1PR3 agonists might be potential therapeutics to protect against sepsis by increasing disease tolerance against infections. Funding: This study was supported by the Center for Sepsis Control and Care (CSCC), the German Research Foundation (DFG), RTG 1715 (to M. H. G. and I. R.) and the National Institutes of Health, Grant R01GM043880 (to S. S.).
