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.
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.
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