Dendritic cells regulate angiogenesis associated with liver fibrogenesis.
During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.
Charité Center 12 Internal Medicine and Dermatology, Reproductive Medicine Research Group, Universitätsmedizin Berlin, Berlin, Germany, sandra.blois@charite.de.
Sandra M
SM
Blois
Flavia
F
Piccioni
Nancy
N
Freitag
Irene
I
Tirado-González
Petra
P
Moschansky
Rodrigo
R
Lloyd
Karin
K
Hensel-Wiegel
Matthias
M
Rose
Mariana G
MG
Garcia
Laura D
LD
Alaniz
Guillermo
G
Mazzolini
D000818:Animals; D039521:CD11c Antigen / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
D039521:CD11c Antigen; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1