IL-19 Is a Novel Lymphangiocrine Factor Inducing Lymphangiogenesis and Lymphatic Junctional Regulation

BACKGROUND: The lymphatic system functions by removing fluid, macromolecules, and immune cells to maintain tissue homeostasis. The structural organization of junctional protein complexes is vital to lymphatic function where initial lymphatics have permeable button junctions and collecting lymphatics have relatively impermeable zipper junctions. During inflammation, this junctional morphology appears to reverse, contributing to overall lymphatic malfunction. Little is known about the effects of immunomodulatory cytokines on lymphatic vessel formation and function during inflammation. The purpose of this study is to test the hypothesis that IL (interleukin)-19 promotes lymphangiogenesis and proper lymphatic function during inflammation. METHODS: We used cultured human dermal lymphatic endothelial cells to determine IL-19 expression and its effects on lymphangiogenesis assays. Immunocytochemistry and electric cell-substrate impedance sensing determined effects on junctional morphology as it relates to permeability in vitro. RNA sequencing determined the effects of IL-19 on gene expression. Il19^-/- Ldlr^-/- double knockout mice were used to determine IL-19 effects on lymphatic function and lymphatic vessel visualization in vivo. RESULTS: Endogenous IL-19 expression is induced by exogenous IL-19 and VEGF (vascular endothelial growth factor) C stimulation. IL-19 is lymphangiogenic, increasing human dermal lymphatic endothelial cell migration, network formation, and proliferation. IL-19 induces expression of transcription factors and permeability-associated genes. IL-19 induces rapid VE-cadherin (vascular endothelial cadherin) phosphorylation, increases permeability of human dermal lymphatic endothelial cell monolayers, and mitigates oxidized low-density lipoprotein-associated decrease in human dermal lymphatic endothelial cell permeability. In vivo, Il19^-/- Ldlr^-/- double knockout mice on a high-fat diet have impaired lymphatic drainage, decreased lymphatic branch points, and increased percentage of zippered junctions compared with control mice. CONCLUSIONS: Taken together, these data show that IL-19 has potent effects on lymphatic vessel formation and function in vitro and that IL-19 regulates lymphatic drainage in vivo. IL-19 may represent an immunomodulatory cytokine with therapeutic potential for improving impaired lymphatic function consequent to inflammation.