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Published on: December 9, 2022
S1P lyase inhibition protects against sepsis by promoting disease tolerance via the S1P/S1PR3 axis
Cynthia Weigel1, Sören S Hüttner2, Kristin Ludwig3
1Department 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.
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.).
Insights
Low-dose epirubicin protects against sepsis by inhibiting S1P lyase (SPL), activating the S1P/S1PR3 pathway. This approach enhances disease tolerance and may offer new sepsis therapeutics.
Area of Science:
- Biomedical research
- Infectious disease
- Pharmacology
Background:
- Sepsis causes one-third of hospital deaths, with limited treatment options beyond antibiotics.
- Low-dose anthracyclines have shown protective effects against sepsis in preclinical models.
- This study explores novel therapeutic strategies targeting sepsis outcomes.
Purpose of the Study:
- To investigate the therapeutic potential of low-dose epirubicin in sepsis.
- To elucidate the molecular mechanisms underlying epirubicin's protective effects in sepsis.
- To identify new therapeutic targets for improving sepsis treatment.
Main Methods:
- Sepsis was induced in mice to evaluate treatment efficacy.
- Key parameters assessed included cytokine expression, cell permeability, autophagy, and survival.
- Results were validated in cell cultures and correlated with human sepsis patient data.
Main Results:
- Epirubicin treatment downregulated sphingosine 1-phosphate (S1P) lyase (SPL), increasing S1P levels.
- Accumulated S1P activated S1P-receptor type 3 (S1PR3), reducing tissue damage via disease tolerance.
- SPL inhibition's protective effects were dependent on S1PR3; sepsis patients showed elevated SPL and lung damage markers.
Conclusions:
- SPL inhibition confers tissue protection in sepsis by activating the S1P/S1PR3 axis.
- SPL inhibitors and S1PR3 agonists represent potential therapeutics for sepsis.
- Enhancing disease tolerance offers a promising strategy for managing sepsis infections.
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