Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis
- Carol M Aherne1,
- Colm B Collins2,
- Joanne C Masterson2,3,
- Marco Tizzano4,
- Theresa A Boyle5,
- Joseph A Westrich1,
- Jason A Parnes4,
- Glenn T Furuta2,3,
- Jesús Rivera-Nieves2,
- Holger K Eltzschig1
- 1Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA
- 2Mucosal Inflammation Program, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
- 3Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA
- 4Department of Cell and Developmental Biology, Rocky Mountain Taste and Smell Centre, University of Colorado, Denver, Aurora, Colorado, USA
- 5Department of Pathology, University of Colorado, Denver, Aurora, Colorado, USA
- Correspondence to Dr Holger K Eltzschig, Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, 12700 E 19th Avenue, Mailstop B112, Research Complex 2, Room 7124, Aurora, CO 80045, USA;
Contributors All authors contributed to data generation, data analysis and interpretation as well as writing of the manuscript.
- Revised 15 June 2011
- Accepted 20 June 2011
- Published Online First 3 August 2011
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.
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.
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