S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis
Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite numerous clinical trials that addressed this syndrome, there is still no causative treatment available to dampen its severity. Curtailing the infection at an early stage with...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-05-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332224004591 |
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| author | Anke C. Ziegler Raphael S. Haider Carsten Hoffmann Markus H. Gräler |
| author_facet | Anke C. Ziegler Raphael S. Haider Carsten Hoffmann Markus H. Gräler |
| author_sort | Anke C. Ziegler |
| collection | DOAJ |
| description | Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite numerous clinical trials that addressed this syndrome, there is still no causative treatment available to dampen its severity. Curtailing the infection at an early stage with anti-infectives is the only effective treatment regime besides intensive care. In search for additional treatment options, we recently discovered the inhibition of the sphingosine 1-phosphate (S1P) lyase and subsequent activation of the S1P receptor type 3 (S1PR3) in pre-conditioning experiments as promising targets for sepsis prevention. Here, we demonstrate that treatment of septic mice with the direct S1P lyase inhibitor C31 or the S1PR3 agonist CYM5541 in the advanced phase of sepsis resulted in a significantly increased survival rate. A single dose of each compound led to a rapid decline of sepsis severity in treated mice and coincided with decreased cytokine release and increased lung barrier function with unaltered bacterial load. The survival benefit of both compounds was completely lost in S1PR3 deficient mice. Treatment of the murine macrophage cell line J774.1 with either C31 or CYM5541 resulted in decreased protein kinase B (Akt) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) phosphorylation without alteration of the mitogen-activated protein kinase (MAPK) p38 and p44/42 phosphorylation. Thus, activation of S1PR3 in the acute phase of sepsis by direct agonism or S1P lyase inhibition dampened Akt and JNK phosphorylation, resulting in decreased cytokine release, improved lung barrier stability, rapid decline of sepsis severity and better survival in mice. |
| first_indexed | 2024-04-24T11:37:56Z |
| format | Article |
| id | doaj.art-010e0b30ea494d14a19a8f95cf48134c |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-24T11:37:56Z |
| publishDate | 2024-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-010e0b30ea494d14a19a8f95cf48134c2024-04-10T04:28:30ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-05-01174116575S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsisAnke C. Ziegler0Raphael S. Haider1Carsten Hoffmann2Markus H. Gräler3Department of Anesthesiology and Intensive Care Medicine, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Str. 2. Jena D-07745, GermanyInstitut für Molekulare Zellbiologie, CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, Jena D-07745, Germany; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, UKInstitut für Molekulare Zellbiologie, CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, Jena D-07745, GermanyDepartment of Anesthesiology and Intensive Care Medicine, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Str. 2. Jena D-07745, Germany; Center for Sepsis Control and Care, Jena University Hospital, Jena 07740, Germany; Correspondence to: Hans-Knöll-Str. 2, Jena 07745, Germany.Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite numerous clinical trials that addressed this syndrome, there is still no causative treatment available to dampen its severity. Curtailing the infection at an early stage with anti-infectives is the only effective treatment regime besides intensive care. In search for additional treatment options, we recently discovered the inhibition of the sphingosine 1-phosphate (S1P) lyase and subsequent activation of the S1P receptor type 3 (S1PR3) in pre-conditioning experiments as promising targets for sepsis prevention. Here, we demonstrate that treatment of septic mice with the direct S1P lyase inhibitor C31 or the S1PR3 agonist CYM5541 in the advanced phase of sepsis resulted in a significantly increased survival rate. A single dose of each compound led to a rapid decline of sepsis severity in treated mice and coincided with decreased cytokine release and increased lung barrier function with unaltered bacterial load. The survival benefit of both compounds was completely lost in S1PR3 deficient mice. Treatment of the murine macrophage cell line J774.1 with either C31 or CYM5541 resulted in decreased protein kinase B (Akt) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) phosphorylation without alteration of the mitogen-activated protein kinase (MAPK) p38 and p44/42 phosphorylation. Thus, activation of S1PR3 in the acute phase of sepsis by direct agonism or S1P lyase inhibition dampened Akt and JNK phosphorylation, resulting in decreased cytokine release, improved lung barrier stability, rapid decline of sepsis severity and better survival in mice.http://www.sciencedirect.com/science/article/pii/S0753332224004591CYM5541C31InflammationCytokineSphingosineReceptor |
| spellingShingle | Anke C. Ziegler Raphael S. Haider Carsten Hoffmann Markus H. Gräler S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis Biomedicine & Pharmacotherapy CYM5541 C31 Inflammation Cytokine Sphingosine Receptor |
| title | S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis |
| title_full | S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis |
| title_fullStr | S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis |
| title_full_unstemmed | S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis |
| title_short | S1PR3 agonism and S1P lyase inhibition rescue mice in the severe state of experimental sepsis |
| title_sort | s1pr3 agonism and s1p lyase inhibition rescue mice in the severe state of experimental sepsis |
| topic | CYM5541 C31 Inflammation Cytokine Sphingosine Receptor |
| url | http://www.sciencedirect.com/science/article/pii/S0753332224004591 |
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