S1PR1 regulates lymphatic valve development and tertiary lymphoid organ formation in the ileum.

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2025-09-01 Epub Date: 2025-06-24 DOI:10.1084/jem.20241799
Xin Geng, Lijuan Chen, Zoheb Ahmed, Guilherme Pedron Formigari, Yen-Chun Ho, Ilaria Del Gaudio, Marcella Neves Datilo, Zheila J Azartash-Namin, Coraline Heron, Xindi Shan, Ravi Shankar Keshari, Soumiya Pal, Hong Chen, Florea Lupu, Lijun Xia, Gwendalyn J Randolph, Scott D Zawieja, Eric Camerer, Michael J Davis, R Sathish Srinivasan
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引用次数: 0

Abstract

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.

S1PR1调节回肠淋巴阀发育和三级淋巴器官形成。
有效的淋巴流动是由淋巴阀(lv)保证的。调控左室发育的机制尚不完全清楚。在这里,我们发现淋巴内皮细胞(LECs)中GPCR鞘氨醇1-磷酸受体1 (S1PR1)的缺失导致LVs减少。有趣的是,留在回肠末梢引流淋巴管中的LVs特别功能失调。此外,突变小鼠回肠末端形成三级淋巴器官(TLOs)。该部位的TLOs与人类和小鼠的回肠炎有关。然而,缺乏S1PR1的小鼠没有出现明显的回肠炎特征。机制上,S1PR1调节剪切应力信号和阀门调节分子FOXC2和connexin-37的表达。重要的是,Foxc2+/-小鼠,淋巴水肿-双支气管炎综合征的模型,也在回肠末端发生TLOs。因此,我们已经发现S1PR1是一个以前未知的LV和TLO发展的调节因子。我们还认为,TLOs是一种亚临床炎症的迹象,可能是由于没有回肠炎的淋巴系统疾病而形成的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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