Abstract
ABSTRACTInflammatory bowel disease (IBD) is a disabling chronic inflammatory disease of the gastrointestinal tract. IBD patients have increased intestinal lymphatic vessel density and recent studies have shown that this may contribute to the resolution of IBD. However, the molecular mechanisms involved in IBD-associated lymphangiogenesis are still unclear. In this study, we established a novel inflammatory lymphangiogenesis model in zebrafish larvae involving colitogenic challenge stimulated by exposure to 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sodium sulphate (DSS). Treatment with either TNBS or DSS resulted in vascular endothelial growth factor receptor (Vegfr)-dependent lymphangiogenesis in the zebrafish intestine. Reduction of intestinal inflammation by the administration of the IBD therapeutic, 5-aminosalicylic acid, reduced intestinal lymphatic expansion. Zebrafish macrophages express vascular growth factors vegfaa, vegfc and vegfd and chemical ablation of these cells inhibits intestinal lymphatic expansion, suggesting that the recruitment of macrophages to the intestine upon colitogenic challenge is required for intestinal inflammatory lymphangiogenesis. Importantly, this study highlights the potential of zebrafish as an inflammatory lymphangiogenesis model that can be used to investigate the role and mechanism of lymphangiogenesis in inflammatory diseases such as IBD.
Highlights
Crohn’s disease and ulcerative colitis are characterised as chronic inflammatory disorders of the gastrointestinal tract and together are known as inflammatory bowel disease (IBD)
The vascular endothelial growth factor receptor (Vegfr) pathway is required for zebrafish intestinal inflammatory lymphangiogenesis As zebrafish macrophages and neutrophils express vegfaa/c/d, we investigated whether the Vegfr pathway is required for zebrafish IIL
In this study, we have shown that trinitrobenzenesulfonic acid (TNBS) and dextran sodium sulphate (DSS)-induced colitogenic challenge results in increased Intestinal lymphatic sprouts (ILSs) development, which we termed zebrafish IIL
Summary
Crohn’s disease and ulcerative colitis are characterised as chronic inflammatory disorders of the gastrointestinal tract and together are known as inflammatory bowel disease (IBD). Reducing inflammatory lymphangiogenesis using a VEGFR-3 blocking antibody, or decreasing lymphatic function through the down regulation of FoxC2, a gene required for lymphatic homeostasis, significantly increases inflammatory oedema and inhibits disease resolution in mouse models of IBD, suggesting a protective role of intestinal lymphatics in IBD (Becker et al, 2015; Jurisic et al, 2013). A recent study has shown that enhancing lymphangiogenesis and lymphatic function, by adenoviral induction of VEGF-C, alleviates experimental chronic intestinal inflammation by increasing inflammatory cell mobilisation and bacterial antigen clearance (D’Alessio et al, 2014). These studies suggest there is potential in treating IBD by improving intestinal lymphatic function, further studies are required to determine the mechanism of IBD-associated lymphangiogenesis
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