Inflammation and Lymphatic Function

Abstract

The lymphatic vasculature plays a crucial role in regulating the inflammatory response by influencing drainage of extravasated fluid, inflammatory mediators, and leukocytes. Lymphatic vessels undergo pronounced enlargement in inflamed tissue and display increased leakiness, indicating reduced functionality. Interfering with lymphatic expansion by blocking the vascular endothelial growth factor C (VEGF-C)/vascular endothelial growth factor receptor 3 (VEGFR-3) signaling axis exacerbates inflammation in a variety of disease models, including inflammatory bowel disease (IBD), rheumatoid arthritis and skin inflammation. In contrast, stimulation of the lymphatic vasculature, e.g., by transgenic or viral overexpression as well as local injections of VEGF-C, has been shown to reduce inflammation severity in models of rheumatoid arthritis, skin inflammation, and IBD. Strikingly, the induced expansion of the lymphatic vasculature improves lymphatic function as assessed by the drainage of dyes, fluorescent tracers or inflammatory cells and labeled antigens. The drainage performance of lymphatic vessels is influenced by vascular permeability and pumping activity, which are influenced by VEGF-C/VEGFR-3 signaling as well as several inflammatory mediators, including TNF-α, IL-1β, and nitric oxide. Considering the beneficial effects of lymphatic activation in inflammation, administration of pro-lymphangiogenic factors like VEGF-C, preferably in a targeted, inflammation site-specific fashion, represents a promising therapeutic approach in the setting of inflammatory pathologies.

Keywords: arthritis; inflammation; inflammatory bowel disease; inflammatory mediators; lymphangiogenesis; lymphatic vessels; psoriasis; skin.

Figure 1

Effects of lymphatic vessel stimulation or inhibition on skin inflammation. Inflamed skin presents with epidermal thickening, edema and infiltration by inflammatory leukocytes (e.g., CD8-positive cells or macrophages and granulocytes). Stimulation of the lymphatic vasculature alleviates inflammation, reducing edema, epidermal thickening and inflammatory infiltration while improving lymphatic drainage, thus lowering the numbers of inflammatory cells in the inflamed skin. Inhibition of the lymphatic vasculature aggravates inflammation and reduces lymphatic clearance.