IL-19 Modifies Lymphatic Flux During Hyperlipidemia - Cardiovascular diseases remain 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 a major cause of cardiovascular
disease: atherosclerosis. Current therapeutics for atherosclerosis fail to consider the role of dampening
inflammation and improving lymphatic function, both of which have the potential to promote plaque regression.
Lymphangiogenesis is the process where the lymphatic network is extended, but its role in atherogenesis is
currently under-characterized and controversial. Inflammatory diseases are found to have lymphangiogenesis
with associated malfunction, but controversy exists as to whether this is a cause of disease pathogenesis or a
compensatory attempt at disease resolution. Recent data suggests a role for lymphatic vessels in reverse
cholesterol transport (RCT), which relies on the junctional morphology between lymphatic endothelial cells
(LECs) to regulate the egression of HDL and/or inflammatory cells. During inflammation, junctions between LECs
transform from discontinuous buttons to impermeable zippers, which may impede RCT and prevent resolution
of inflammation. Our lab has previously reported that Interleukin-19 (IL-19), an immuno-modulatory cytokine,
uniquely attenuates atherosclerotic plaque progression while also being pro-angiogenic. This drives our central
hypothesis that one mechanism whereby IL-19 prevents atherosclerotic disease progression is by driving
functional lymphangiogenesis, especially through the maintenance of permeable lymphatic vessels to promote
RCT. Our in vitro data indicates IL-19 can significantly induce primary LEC proliferation, migration, and tube
formation, all lymphangiogenic assays. RNA sequencing also identified upregulation of Prox1, the master
transcription factor of lymphangiogenesis, 6.2-fold. IL-19 also increases expression of several genes implicated
in endothelial cell permeability, including Angpt2. Functional in vitro permeability assays showed that oxLDL
decreases LEC permeability which IL-19 treatment prevents. This suggested that IL-19 can promote transport
of lipid through lymphatic vessels and was confirmed with HDL transit. Junctional morphology was also validated
via immunocytochemistry for VE-cadherin on hdLECs. Western blot confirmed phosphorylation of STAT3, a
factor in canonical IL-19 signaling, and VE-cadherin, an indication of LEC permeability. Subsequent Prox1 siRNA
knockdown mitigated both IL-19 stimulated lymphangiogenesis and Angpt2 upregulation. Preliminary in vivo data
with VEcadCreERT2 Prox1 F/+ mice, which experience compromised lymphatic function, indicates that IL-19
improves lymphatic function through removal of Evans blue dye. These data suggest that IL-19 increases
lymphatic vessel formation and function, with a potential mechanism of enhancing RCT to decrease plaque
burden in atherosclerosis. This grant will continue to characterize IL-19’s mechanistic pathway in LECs and
determine lymphatic functionality in vivo through HDL and foam cell trafficking by aortic microlymphangiography.
