VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes

Lymphangiogenesis is involved in tumor cell metastasis and plays a major role in chronic inflammatory disorders. To investigate the role of lymphangiogenesis in inflammation, we induced and maintained delayed-type hypersensitivity (DTH) reactions in the ears of mice and then analyzed the resulting lymphangiogenesis in the inflamed tissue and draining lymph nodes (LNs) by quantitative fluorescence-activated cell sorting (FACS) and by immunofluorescence. Long-lasting inflammation induced a significant increase in the number of lymphatic endothelial cells, not only in the inflamed ears but also in the ear-draining auricular LNs. Inflammation-induced lymphangiogenesis was potently blocked by systemic administration of a vascular endothelial growth factor (VEGF)-A neutralizing antibody. Surprisingly, tissue inflammation specifically induced LN lymphangiogenesis but not LN angiogenesis. These findings were explained by analysis of both VEGF-A protein and mRNA levels, which revealed that VEGF-A was expressed at high mRNA and protein levels in inflamed ears but that expression was increased only at the protein level in activated LNs. Inflammation-induced lymphangiogenesis in LNs was independent of the presence of nodal B lymphocytes, as shown in B cell-deficient mice. Our data reveal that chronic inflammation actively induces lymphangiogenesis in LNs, which is controlled remotely, by lymphangiogenic factors produced at the site of inflammation.