Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis

• Published in: Gut Vol. 61; no. 5; pp. 695 - 705
• Main Authors: Aherne, Carol M, Collins, Colm B, Masterson, Joanne C, Tizzano, Marco, Boyle, Theresa A, Westrich, Joseph A, Parnes, Jason A, Furuta, Glenn T, Rivera-Nieves, Jesús, Eltzschig, Holger K
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.05.2012; BMJ Publishing Group; BMJ Publishing Group LTD; BMJ Group
• Series: Original article
• Subjects: Acute Disease; Animals; Apoptosis; Biological and medical sciences; Biomarkers - metabolism; Cell Line; Colitis - immunology; Colitis - metabolism; Colon; Disease Models, Animal; epithelial permeability; Gastroenterology. Liver. Pancreas. Abdomen; Inflammation; Inflammatory Bowel Disease; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - metabolism; inflammatory cells; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Leukocytes; Medical sciences; Mice; Mice, Inbred C57BL; mucosal immunology; Nerve Growth Factors - administration & dosage; Nerve Growth Factors - metabolism; Netrin-1; Neutrophil Infiltration; Neutrophils; Permeability; Recruitment; Rodents; Studies; Transendothelial and Transepithelial Migration; Tumor necrosis factor-TNF; Tumor Suppressor Proteins - administration & dosage; Tumor Suppressor Proteins - metabolism; Ulcerative colitis; Variance analysis; Guidance; Acute; Gastroenterology; Digestive diseases; Intestinal disease; Inflammatory cell; Colitis
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2011-300012

BackgroundInflammatory 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.DesignDSS-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.ResultsConsistent 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.ConclusionsThe present study identifies a previously unrecognised role for netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking.