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IL-19 Modifies Lymphatic Flux During Hyperlipidemia

Award Number: F30HL172580
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/16/2024
PERIOD OF PERFORMANCE END DATE: 09/15/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $35,367 )
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	9/2/2025	NON-COMPETING CONTINUATION	$35,367
														Subtotal = $35,367

Issue Date FY: 2024 ( Subtotal = $34,803 )
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	1	9/10/2024	NEW	$0
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	9/10/2024	NEW	$34,803
														Subtotal = $34,803

Grand Total All Awards = $70,170

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IL-19 Modifies Lymphatic Flux During Hyperlipidemia

Award Number: F30HL172580

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/16/2024

PERIOD OF PERFORMANCE END DATE: 09/15/2028

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