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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 (M?) plasticity and activation both in cultured M?s and in vivo, imparting a hybrid M1-M2 phenotype. The protective function of VEGF-C was meditated by the so-called resolving M?s 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.

SUBMITTER: D'Alessio S 

PROVIDER: S-EPMC4151217 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

D'Alessio Silvia S   Correale Carmen C   Tacconi Carlotta C   Gandelli Alessandro A   Pietrogrande Giovanni G   Vetrano Stefania S   Genua Marco M   Arena Vincenzo V   Spinelli Antonino A   Peyrin-Biroulet Laurent L   Fiocchi Claudio C   Danese Silvio S  

The Journal of clinical investigation 20140808 9


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 reduce  ...[more]

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