Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis
Objective—Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apo AI, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF.
Approach and Results—TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apo AI attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apo AI reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. Apo AI also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. Apo AI also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice.
Conclusions—Apo AI restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein–based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature.
- Received April 1, 2014.
- Accepted August 25, 2015.
- © 2015 American Heart Association, Inc.