Article Text
Abstract
Background Inflammatory bowel diseases, encompassing Crohn's disease and ulcerative colitis, are characterised by persistent leucocyte tissue infiltration leading to perpetuation of an inappropriate inflammatory cascade. The neuronal guidance molecule netrin-1 has recently been implicated in the orchestration of leucocyte trafficking during acute inflammation. We therefore hypothesised that netrin-1 could modulate leucocyte infiltration and disease activity in a model of inflammatory bowel disease.
Design DSS-colitis was performed in mice with partial genetic netrin-1 deficiency (Ntn-1+/− mice) or wild-type mice treated with exogenous netrin-1 via osmotic pump to examine the role of endogenous and therapeutically administered netrin-1. These studies were supported by in vitro models of transepithelial migration and intestinal epithelial barrier function.
Results Consistent with our hypothesis, we observed induction of netrin-1 during intestinal inflammation in vitro or in mice exposed to experimental colitis. Moreover, mice with partial netrin-1 deficiency demonstrated an exacerbated course of DSS-colitis compared to littermate controls, with enhanced weight loss and colonic shortening. Conversely, mice treated with exogenous mouse netrin-1 experienced attenuated disease severity. Importantly, permeability studies and quantitative assessment of apoptosis reveal that netrin-1 signalling events do not alter mucosal permeability or intestinal epithelial cell apoptosis. In vivo studies of leucocyte transmigration demonstrate suppression of neutrophil trafficking as a key function mediated by endogenous or exogenously administered netrin-1. Finally, genetic studies implicate the A2B adenosine receptor in netrin-1-mediated protection during DSS-colitis.
Conclusions The present study identifies a previously unrecognised role for netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking.
- Ulcerative colitis
- mucosal immunology, inflammatory cells, epithelial permeability
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Footnotes
Original data related to this publication are available upon request.
Funding The present manuscript is supported by United States National Institutes of Health grant R01-HL0921, R01-DK083385 and R01HL098294 to HKE, and Crohn's and Colitis Foundation Senior Research Award to HKE. Supported by Crohn's and Colitis Foundation Fellowship to CMA, CBC and JCM. Supported in part by the Histology and Imaging Core of NIDCD Grant P30 DC04657 to D. Restrepo and T. Finger.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.