IL‐19 Regulates Atherosclerotic Plaque Progression via Lymphangiogenesis

Abstract

IntroductionCardiovascular diseases are the leading cause of deaths globally, representing approximately 31% of deaths per year, 85% of which are due to myocardial infarction (MI) or stroke. This does not account for the millions of patients suffering daily with current therapies that are not efficacious in treating the root cause of MI and stroke, atherosclerosis, by reducing inflammation or increasing reverse cholesterol transport (RCT). Atherosclerosis is a vascular inflammatory disease characterized by the formation of fatty plaques which can rupture, leading vessel occlusion. Lymphangiogenesis is the process whereby lymphatic vessels are generated, but its role in atherogenesis is currently under‐characterized and controversial. It has been suggested that lymphangiogenesis is either protective by promoting plaque regression through RCT or it is deleterious by promoting plaque instability through white blood cell trafficking. Our lab has 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 driving lymphangiogenesis, allowing attenuation of plaque progression.Methods & ResultsSeveral approaches were performed to test the hypothesis that IL‐19 is lymphangiogenic. 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 chemokine expression as well as an angiogenic transcriptional program in LECs. Notably it induces expression of Prox1, a master transcription factor of lymphangiogenesis, 6.2‐fold. The increases of chemokine and transcription factor expression from RNAseq were verified through qPCR analysis. To further analyze the translational effects of IL‐19, we utilized an LDL Receptor Knockout (LDLR‐/‐) 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 associated with the known decrease IL‐19 causes in atherosclerotic plaque progression.Conclusion & SummaryThese data suggest that IL‐19 increases lymphatic vessel formation, potentially allowing RCT to take place to decrease plaque burden in atherosclerosis. Further studies will confirm IL‐19’s mechanistic pathway in LECs. We will also determine RCT and inflammatory cell trafficking by intravital microscopy. These results have the potential to shift our understanding toward a positive view of the association between the lymphatic system and atherosclerosis.