Abstract 13070: Interleukin-19 Regulates Lymphatic Permeability and Induces Prox1-Dependent Lymphangiogenesis

Abstract

Introduction: Increased lymphangiogenesis is associated with atherosclerosis, but whether it is disease-causative or a compensatory attempt to attenuate disease is currently unresolved. Recent studies suggest lymphatic permeability plays a role in reverse cholesterol transport (RCT) as a possible mechanism for attenuating atherosclerosis. We previously reported that that Interleukin-19 (IL-19), an immunomodulatory cytokine, is unique by inducing angiogenesis while reducing atherosclerosis. The purpose of this study was to test the hypothesis that IL-19 could be atheroprotective by inducing functional lymphangiogenesis and promoting lymphatic flux. Methods & Results: RNA sequencing of IL-19-treated human Lymphatic Endothelial Cells (hLEC) identified induction of chemokines, pro-lymphangiogenic, and permeability-associated genes. Prox1, the master regulator of lymphatic formation, was increased by six-fold, validated by qPCR and western blot. Cellular assays further demonstrated IL-19-associated lymphangiogenesis through hLEC proliferation, migration, and tube formation, each mitigated by Prox1 siRNA knockdown. Angpt2, a regulator of permeability through VE-cadherin, is also upregulated by IL-19 and mitigated by Prox1 siRNA knockdown. Electric Cell-substrate Impedance Sensing (ECIS) showed that IL-19 mitigates oxLDL-associated decreases in permeability, suggestive of preventing lymphatic barrier malfunction during atherosclerosis. Preliminary in vivo lymphatic permeability assays suggest injection of rmIL-19 improves lymphatic function in conditional lymphatic-specific Prox1 heterozygous mice. Conversely, similar experiments show that Il19 / LDLR double knockout mice, which are known to have exacerbated atherosclerosis, also have significantly decreased lymphatic permeability compared to LDLR -/- mice after 16-weeks of high fat diet. Conclusion: These data suggest that IL-19 is a previously unrecognized regulator of lymphatic function as it increases lymphangiogenesis and permeability, with the potential to improve RCT. Together, these effects may regulate atherosclerosis, and influence our understanding of the association between the lymphatic system and atherosclerosis.