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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

123 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)3863-3878
Numero di pagine16
RivistaTHE JOURNAL OF CLINICAL INVESTIGATION
Volume124
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Animals
  • Colon
  • Disease Models, Animal
  • Female
  • Humans
  • Inflammatory Bowel Diseases
  • Lymphangiogenesis
  • Lymphatic Vessels
  • Macrophage Activation
  • Macrophages
  • Male
  • Medicine (all)
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3

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