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

CM Aherne, CB Collins, JC Masterson, M Tizzano… - Gut, 2012 - gut.bmj.com
CM Aherne, CB Collins, JC Masterson, M Tizzano, TA Boyle, JA Westrich, JA Parnes…
Gut, 2012gut.bmj.com
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 …
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.
gut.bmj.com