VEGF-C–dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease
Silvia D’Alessio, … , Claudio Fiocchi, Silvio Danese
Silvia D’Alessio, … , Claudio Fiocchi, Silvio Danese
Published August 8, 2014
Citation Information: J Clin Invest. 2014;124(9):3863-3878. https://doi.org/10.1172/JCI72189.
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Research Article Vascular biology

VEGF-C–dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology that are associated with an aberrant mucosal immune response. Neoangiogenesis and vascular injury are observed in IBD along with increased lymphangiogenesis. While the pathogenic role of angiogenesis in IBD is well characterized, it is not clear how or if increased lymphangiogenesis promotes disease. Here, we determined that enhancing lymphangiogenesis and lymphatic function reduces experimental IBD. Specifically, we demonstrated that adenoviral induction of prolymphangiogenic factor VEGF-C provides marked protection against the development of acute and chronic colitis in 2 different animal models. VEGF-C–dependent protection was observed in combination with increased inflammatory cell mobilization and bacterial antigen clearance from the inflamed colon to the draining lymph nodes. Moreover, we found that the VEGF-C/VEGFR3 pathway regulates macrophage (MΦ) plasticity and activation both in cultured MΦs and in vivo, imparting a hybrid M1-M2 phenotype. The protective function of VEGF-C was meditated by the so-called resolving MΦs during chronic experimental colitis in a STAT6-dependent manner. Together, these findings shed light on the contribution of lymphatics to the pathogenesis of gut inflammation and suggest that correction of defective lymphatic function with VEGF-C has potential as a therapeutic strategy for IBD.

Authors

Silvia D’Alessio, Carmen Correale, Carlotta Tacconi, Alessandro Gandelli, Giovanni Pietrogrande, Stefania Vetrano, Marco Genua, Vincenzo Arena, Antonino Spinelli, Laurent Peyrin-Biroulet, Claudio Fiocchi, Silvio Danese

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Figure 5

Systemic delivery of VEGF-C markedly increases lymphatic drainage and mobilization of inflammatory cells from the inflamed colon to DLNs.

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Systemic delivery of VEGF-C markedly increases lymphatic drainage and mo...
(A) 10 μg of Evans blue dye was injected into the colonic mucosa of healthy (UN, n = 4/time point), Ad-hVEGF-C– (n = 5/time point), and mF431C1-treated mice (n = 5/time point) undergoing 2 cycles of DSS treatment. Mice treated with DSS alone (n = 5/time point) were used as a control group. Evans blue was then extracted 16 hours after the dye injection from distal colons of comparable weight. Graph shows the total dye remaining in the colon expressed in μg. Data represent the mean per group ± SEM. Black dashed lines represent the 2 DSS cycles. (B–D) GFP+ peritoneal inflammatory cells (~106 cells) were injected into the rectal mucosa of the inflamed and noninflamed colons of healthy (UN, n = 5) and DSS-treated mice (n = 5 per experimental group, at day 5 after the second DSS cycle) and IL-10 WT (n = 4) and IL-10–KO mice (n = 4 per group at day 21 after the first Ad-hVEGF-C administration). Twelve hours later, the DLNs were sampled and sectioned for histologic and FACS analysis. (C) Upper panels: Representative frozen sections of DLNs from the indicated experimental groups coimmunostained for LYVE1 (red) and DAPI (blue) and merged. Lower panels: Representative FACS from the indicated groups. The number in each FACS histogram represents the percentage of GFP+ cells. Scale bar: 50 μm. (D) GFP+ inflammatory cells in the entire frozen section were quantified and are presented as AU. Error bars represent the mean per group ± SEM. *P < 0.05; **P < 0.001.