S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity
G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by protecting the integrity of the endothelial barrier without affecting immune cell egress. Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment.
Authors
- Kexin Wang (ORCID: https://orcid.org/0009-0006-4417-7731)
- Liuwang Gao
- Zhenhua Shao (ORCID: https://orcid.org/0000-0001-7204-801X)
- Hu Zhang (ORCID: https://orcid.org/0000-0002-3281-4661)
- Zhongwei Cao (ORCID: https://orcid.org/0000-0001-8778-4327)
- Huaping Zheng (ORCID: https://orcid.org/0000-0002-0716-8987)
- Yuqi Zhao (ORCID: https://orcid.org/0000-0003-3424-2852)
- Jie Zhao (ORCID: https://orcid.org/0000-0002-6370-9549)
- Kun Zheng (ORCID: https://orcid.org/0000-0001-5814-1904)
- Cheng Deng (ORCID: https://orcid.org/0000-0002-5296-8879)
- Juergen Brosius (ORCID: https://orcid.org/0000-0003-1650-2059)
- Xiaowen Tian (ORCID: https://orcid.org/0000-0001-7520-1075)
- Wei Li (ORCID: https://orcid.org/0000-0002-9025-7293)
- Zhen Zeng (ORCID: https://orcid.org/0000-0002-2213-0696)
- Kang Zhang (ORCID: https://orcid.org/0000-0002-4549-1697)
- Jingqiu Cheng
- Jingjing Yu (ORCID: https://orcid.org/0000-0001-5822-4486)
- Wei Yan (ORCID: https://orcid.org/0000-0001-9825-0689)
- Fengming Luo (ORCID: https://orcid.org/0000-0002-7659-4621)
- Zheng Xu (ORCID: https://orcid.org/0000-0002-5374-4121)
- Huajing Wan (ORCID: https://orcid.org/0000-0002-6041-8877)
- Xiaoju Tang
Institutions
- Macau University of Science and Technology (MO)
- Chengdu Medical College (CN)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1038/s41467-025-57124-x
- Citations
- 13
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Sichuan University
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- National Science and Technology Major Project
- West China Hospital, Sichuan University