S1PR1 regulates lymphatic valve development and tertiary lymphoid organ formation in the ileum
Efficient lymph flow is ensured by lymphatic valves (LVs). The mechanisms that regulate LV development are incompletely understood. Here, we show that the deletion of the GPCR sphingosine 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs) results in fewer LVs. Interestingly, LVs that remained in the terminal ileum-draining lymphatic vessels were specifically dysfunctional. Furthermore, tertiary lymphoid organs (TLOs) formed in the terminal ileum of the mutant mice. TLOs in this location are associated with ileitis in humans and mice. However, mice lacking S1PR1 did not develop obvious characteristics of ileitis. Mechanistically, S1PR1 regulates shear stress signaling and the expression of the valve-regulatory molecules FOXC2 and connexin-37. Importantly, Foxc2+/- mice, a model for lymphedema-distichiasis syndrome, also develop TLOs in the terminal ileum. Thus, we have discovered S1PR1 as a previously unknown regulator of LV and TLO development. We also suggest that TLOs are a sign of subclinical inflammation that can form due to lymphatic disorders in the absence of ileitis.
Authors
- Lijun Xia (ORCID: https://orcid.org/0000-0002-9586-7971)
- Marcella Neves Dátilo (ORCID: https://orcid.org/0000-0001-6763-3337)
- Yen‐Chun Ho (ORCID: https://orcid.org/0000-0001-9147-2502)
- Xindi Shan (ORCID: https://orcid.org/0000-0003-3951-8766)
- Ilaria Del Gaudio (ORCID: https://orcid.org/0000-0001-6794-8291)
- Ravi S. Keshari (ORCID: https://orcid.org/0000-0002-4177-9095)
- Scott D. Zawieja (ORCID: https://orcid.org/0000-0003-4658-3179)
- Soumiya Pal (ORCID: https://orcid.org/0000-0002-8003-9866)
- Florea Lupu (ORCID: https://orcid.org/0000-0003-1249-9278)
- R. Sathish Srinivasan (ORCID: https://orcid.org/0000-0002-4465-3340)
- Hong Chen (ORCID: https://orcid.org/0000-0002-1906-6611)
- Lijuan Chen
- Coraline Heron (ORCID: https://orcid.org/0000-0002-3376-0685)
- Eric Camerer (ORCID: https://orcid.org/0000-0002-6271-7125)
- Zoheb Ahmed
- Gwendalyn J. Randolph (ORCID: https://orcid.org/0000-0001-9045-1195)
- Zheila J. Azartash-Namin
- Michael J. Davis (ORCID: https://orcid.org/0000-0002-7992-9300)
- Guilherme Pedron Formigari (ORCID: https://orcid.org/0000-0002-8028-7480)
- Xin Geng
Institutions
- Boston Children's Hospital (US)
- Inserm (FR)
- Washington University in St. Louis (US)
- Université Paris Cité (FR)
- Oklahoma Medical Research Foundation (US)
- Paris Cardiovascular Research Center (FR)
- University of Oklahoma Health Sciences Center (US)
- University of Missouri (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1084/jem.20241799
- Citations
- 7
- Primary Topic
- Lymphatic System and Diseases
- Type
- article
- Field-Weighted Citation Impact
- 7.32
Funders
- Tobacco Settlement Endowment Trust
- Agence Nationale de la Recherche
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences