Abstract 497: IL-19 Induces Lymphangiogenesis Through A Prox1-dependent Mechanism

Introduction: The role of lymphangiogenesis in atherogenesis is currently under-characterized and controversial. It has been suggested that lymphangiogenesis is either protective by promoting plaque regression through reverse cholesterol transport (RCT) or deleterious by promoting plaque instability through white blood cell trafficking. We have previously reported that Interleukin-19 (IL-19), an anti-inflammatory cytokine, uniquely attenuates atherosclerotic plaque progression while also being pro-angiogenic. This drives our hypothesis that one mechanism whereby IL-19 is atheroprotective is by promoting lymphangiogenesis. Methods & Results: IL-19 can significantly induce primary human lymphatic endothelial cell (LEC) proliferation, migration, and tube formation, all angiogenic assays, to the same degree as VEGF-C, a known mediator of lymphangiogenesis. RNA sequencing (RNAseq) analysis indicates that IL-19 induces expression of chemokines as well as several angiogenic transcription factors in LECs. Notably, it induces expression of Prox1, a master transcription factor of lymphangiogenesis, 6.2-fold. The increases seen in chemokine and transcription factor expression from RNAseq were verified through qPCR analysis. Subsequent Prox1 siRNA knockdown prevented IL-19 associated LEC proliferation and migration. We then utilized an LDL Receptor Knockout mouse model fed a high fat diet for 16-weeks with daily injections of either recombinant mouse IL-19 or saline. Preliminary results suggest an increase in lymphatic vessel presence is associated with the known decrease IL-19 causes in atherosclerotic plaque progression. Transendothelial resistance assays were performed to determine IL-19's effect on lymphatic cell permeability. Preliminary data suggests that IL-19 alters LEC resistance, indicative of permeability and possibly RCT. We will also continue to evaluate RCT and inflammatory cell trafficking via intravital microscopy. Conclusion: These data suggest that IL-19 increases lymphatic vessel formation, likely through a Prox1-dependent mechanism. These results have the potential to shift our understanding toward a positive view of lymphangiogenesis and attenuation of atherosclerosis.