Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability
ABSTRACT Sepsis is a life‐threatening disease characterized by multiorgan dysfunction caused by an abnormal immune response to microbial infection. Sphingosine‐1‐phosphate (S1P) levels are significantly lower in patients with sepsis and are negatively correlated with the severity of sepsis. However,...
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Wiley
2025-06-01
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| Online Access: | https://doi.org/10.1002/mco2.70238 |
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| author | Suhong Duan Seung‐Gook Kim Jiaying Bao Hyung‐Jin Lim Joon Woo Kim Sung‐Il Yoon Young Jun Park Sanguk Yun Kye‐Seong Kim Hwa‐Ryung Song Myeong Jun Choi Myung‐Kwan Han |
| author_facet | Suhong Duan Seung‐Gook Kim Jiaying Bao Hyung‐Jin Lim Joon Woo Kim Sung‐Il Yoon Young Jun Park Sanguk Yun Kye‐Seong Kim Hwa‐Ryung Song Myeong Jun Choi Myung‐Kwan Han |
| author_sort | Suhong Duan |
| collection | DOAJ |
| description | ABSTRACT Sepsis is a life‐threatening disease characterized by multiorgan dysfunction caused by an abnormal immune response to microbial infection. Sphingosine‐1‐phosphate (S1P) levels are significantly lower in patients with sepsis and are negatively correlated with the severity of sepsis. However, whether the S1P signaling pathway is a target for sepsis treatment remains unknown. Here, we show that our newly synthesized phytosphingosine‐3,4‐cyclic phosphate (3,4‐cPP), a functional agonist of S1P receptor 1 (S1P1), exerts a strong protective effect against severe cecal ligation and puncture (CLP)‐induced sepsis. 3,4‐cPP persistently activates S1P1 without inducing internalization. 3,4‐cPP upregulates SIRT1 expression in macrophages and endothelial cells via S1P1 activation. Additionally, 3,4‐cPP decreases serum levels of proinflammatory cytokines, including IL‐6 and TNF‐α, and inhibits endothelial permeability in CLP‐induced septic mice. Conditional knockout of SIRT1, an NAD+‐dependent deacetylase, in macrophages or endothelial cells counteracts the inhibition of inflammatory cytokine secretion and prevention of endothelial cell permeability by 3,4‐cPP in CLP‐induced septic mice, indicating that the S1P1/SIRT1 axis in both the endothelium and macrophages is essential for survival in sepsis. Collectively, the data suggest that prolonged activation of the S1P1/SIRT1 signaling pathway protects against sepsis by inhibiting hyperinflammation and vascular hyperpermeability. |
| format | Article |
| id | doaj-art-1f2f7aa5246c41818aacf163e6fdb0c5 |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-1f2f7aa5246c41818aacf163e6fdb0c52025-08-20T03:39:28ZengWileyMedComm2688-26632025-06-0166n/an/a10.1002/mco2.70238Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular HyperpermeabilitySuhong Duan0Seung‐Gook Kim1Jiaying Bao2Hyung‐Jin Lim3Joon Woo Kim4Sung‐Il Yoon5Young Jun Park6Sanguk Yun7Kye‐Seong Kim8Hwa‐Ryung Song9Myeong Jun Choi10Myung‐Kwan Han11Department of Microbiology Jeonbuk National University Medical School Jeonju‐si Jeollabuk‐do Republic of KoreaDepartment of Microbiology Jeonbuk National University Medical School Jeonju‐si Jeollabuk‐do Republic of KoreaDepartment of Microbiology Jeonbuk National University Medical School Jeonju‐si Jeollabuk‐do Republic of KoreaDepartment of Microbiology Jeonbuk National University Medical School Jeonju‐si Jeollabuk‐do Republic of KoreaAxceso Biopharma, 282 Hagui‐ro Yongin‐si Gyeonggi‐do Republic of KoreaAxceso Biopharma, 282 Hagui‐ro Yongin‐si Gyeonggi‐do Republic of KoreaAxceso Biopharma, 282 Hagui‐ro Yongin‐si Gyeonggi‐do Republic of KoreaDepartment of Biotechnology Inje University Gimhae Republic of KoreaGraduate School of Biomedical Science and Engineering Hanyang University Seongdong‐gu Seoul Republic of KoreaDepartment of Microbiology Jeonbuk National University Medical School Jeonju‐si Jeollabuk‐do Republic of KoreaAxceso Biopharma, 282 Hagui‐ro Yongin‐si Gyeonggi‐do Republic of KoreaDepartment of Microbiology Jeonbuk National University Medical School Jeonju‐si Jeollabuk‐do Republic of KoreaABSTRACT Sepsis is a life‐threatening disease characterized by multiorgan dysfunction caused by an abnormal immune response to microbial infection. Sphingosine‐1‐phosphate (S1P) levels are significantly lower in patients with sepsis and are negatively correlated with the severity of sepsis. However, whether the S1P signaling pathway is a target for sepsis treatment remains unknown. Here, we show that our newly synthesized phytosphingosine‐3,4‐cyclic phosphate (3,4‐cPP), a functional agonist of S1P receptor 1 (S1P1), exerts a strong protective effect against severe cecal ligation and puncture (CLP)‐induced sepsis. 3,4‐cPP persistently activates S1P1 without inducing internalization. 3,4‐cPP upregulates SIRT1 expression in macrophages and endothelial cells via S1P1 activation. Additionally, 3,4‐cPP decreases serum levels of proinflammatory cytokines, including IL‐6 and TNF‐α, and inhibits endothelial permeability in CLP‐induced septic mice. Conditional knockout of SIRT1, an NAD+‐dependent deacetylase, in macrophages or endothelial cells counteracts the inhibition of inflammatory cytokine secretion and prevention of endothelial cell permeability by 3,4‐cPP in CLP‐induced septic mice, indicating that the S1P1/SIRT1 axis in both the endothelium and macrophages is essential for survival in sepsis. Collectively, the data suggest that prolonged activation of the S1P1/SIRT1 signaling pathway protects against sepsis by inhibiting hyperinflammation and vascular hyperpermeability.https://doi.org/10.1002/mco2.70238cecal ligation and puncturephytosphingosine‐3,4‐cyclic phosphatesepsissirtuin 1 (SIRT1)sphingosine‐1‐phosphatesphingosine‐1‐phosphate receptor 1 |
| spellingShingle | Suhong Duan Seung‐Gook Kim Jiaying Bao Hyung‐Jin Lim Joon Woo Kim Sung‐Il Yoon Young Jun Park Sanguk Yun Kye‐Seong Kim Hwa‐Ryung Song Myeong Jun Choi Myung‐Kwan Han Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability MedComm cecal ligation and puncture phytosphingosine‐3,4‐cyclic phosphate sepsis sirtuin 1 (SIRT1) sphingosine‐1‐phosphate sphingosine‐1‐phosphate receptor 1 |
| title | Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability |
| title_full | Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability |
| title_fullStr | Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability |
| title_full_unstemmed | Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability |
| title_short | Persistent Activation of Sphingosine‐1‐Phosphate Receptor 1 by Phytosphingosine‐3,4‐Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability |
| title_sort | persistent activation of sphingosine 1 phosphate receptor 1 by phytosphingosine 3 4 cyclic phosphate ameliorates sepsis by inhibiting hyperinflammation and vascular hyperpermeability |
| topic | cecal ligation and puncture phytosphingosine‐3,4‐cyclic phosphate sepsis sirtuin 1 (SIRT1) sphingosine‐1‐phosphate sphingosine‐1‐phosphate receptor 1 |
| url | https://doi.org/10.1002/mco2.70238 |
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