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.
View: Text | PDF
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

×

Figure 8

The VEGF-C/VEGFR3 pathway regulates in vivo and in vitro MΦ plasticity and activation.

Options: View larger image (or click on image) Download as PowerPoint
The VEGF-C/VEGFR3 pathway regulates in vivo and in vitro MΦ plasticity a...
(A and B) Mice undergoing 2 cycles of DSS treatment were injected with Ad-hVEGF-C or anti-VEGFR3 Ab. Colonic expression of M2 (A) and M1 (B) MΦ-associated genes was examined by real-time PCR analysis for Ym1, Arg1, Fizz1, Cox2, and iNOS; by ELISA for IL-10; and by FACS for MHCII and CD80 after 24 hours in vitro. Data represent the means ± SEM per group (n = 4–6/group). (A and B) **P < 0.01 versus DSS alone. (C and D) BM-derived MΦs were cultured and stimulated in vitro with LPS (M1), IL-4 (M2), VEGF-C, and VEGF-C plus mF431C1 for 24 hours. Expression of the indicated genes was then examined by real-time PCR, ELISA, or FACS. Data represent the means ± SEM of 3 independent experiments. **P < 0.01 versus untreated (UN); §P < 0.001 versus VEGF-C alone.