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


    Aherne, Carol M. and Collins, Colm B. and Masterson, Joanne C. and Tizzano, Marco and Boyle, Theresa A. and Westrich, Joseph A. and Parnes, Jason A. and Furuta, Glenn T. and Rivera-Nieves, Jesus and Eltzschig, Holger K. (2012) Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis. Gut, 61 (5). pp. 695-705. ISSN 1468-3288

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    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.

    Item Type: Article
    Keywords: Neuronal guidance; molecule netrin-1; attenuates; inflammatory cell; trafficking; acute; experimental colitis;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12496
    Identification Number: https://doi.org/10.1136/gutjnl-2011-300012
    Depositing User: Joanne Masterson
    Date Deposited: 27 Feb 2020 15:50
    Journal or Publication Title: Gut
    Publisher: BMJ Publishing Group
    Refereed: Yes
    URI:

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