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.
Halin
Cornelia
C
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
Tobler
Nadja E
NE
Vigl
Benjamin
B
Brown
Lawrence F
LF
Detmar
Michael
M
D000818:Animals; D002908:Chronic Disease; D017449:Dermatitis, Allergic Contact / Q000473:pathology; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D042583:Lymphangiogenesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D012867:Skin / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse