8 research outputs found
Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis
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