All transcripts were created with artificial intelligence software and modified with manual review by a third party. Although we make every effort to ensure accuracy with the manual review, some may contain computer-generated mistranslations resulting in inaccurate or nonsensical word combinations, or unintentional language. FASEB and the presenting speakers did not review the transcripts and are not responsible and will not be held liable for damages, financial or otherwise, that occur as a result of transcript inaccuracies.
Lymphatic Endothelial Cell S1PR1 Regulates Tertiary Lymphoid Structure Formation in the Mesentery
Sathish Srinivasan from the Oklahoma Medical Research Foundation.The lymphatic vasculature consists of blind-ended capillaries that collect interstitial fluid, digested lipids and immune cells (collectively known as lymph), collecting lymphatic vessels that transport lymph, lymphatic valves that regulate the unidirectional fluid flow and lymphovenous valves that regulate lymph return to blood circulation. Defects in valves are associated with lymphatic disorders such as primary lymphedema and chylous ascites. Oscillatory shear stress is considered as the most upstream regulator of valve development as it activates the expression of critical valve-regulatory molecules such as FOXC2 and connexin-37. However, the mechanisms that sense and transduce mechanical signals to biochemical signals are poorly understood. The physiological and immunological consequences of valve defects are also not fully understood. Here, we show that the GPCR sphingosine-1 phosphate receptor 1 (S1PR1) is a previously unknown regulator of valve development. We also show that the deletion of S1PR1 results in the formation of tertiary lymphoid structures (TLO) in the terminal ileum of adult mice. Mechanistically, S1P produced by lymphatic endothelial cells activates S1PR1 signaling in an autocrine manner. S1PR1 functions as a mechanosensory molecule that regulates the expression of FOXC2 and connexin-37 in response to oscillatory shear stress. We show that a subset of Foxc2+/- mice also develop TLOs, thus recapitulating the phenotype of human lymphedema-distichiasis patients with dysfunctional valves that are caused by heterozygous loss-of-function mutations in FOXC2. In summary, we have identified a novel clinically relevant mechanism that connects lymphatic valves and TLO formation in the gut.
Speakers
Sathish Srinivasan