title: Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis.
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.
  
  
  METHODS
  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.
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Aherne
authors.forename: Colm B
authors.initials: CB
authors.lastname: Collins
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Masterson
authors.forename: Marco
authors.initials: M
authors.lastname: Tizzano
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Boyle
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Westrich
authors.forename: Jason A
authors.initials: JA
authors.lastname: Parnes
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Furuta
authors.forename: Jesús
authors.initials: J
authors.lastname: Rivera-Nieves
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D003092:Colitis / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000378:metabolism*; D000075388:Netrin-1; D020556:Neutrophil Infiltration; D010539:Permeability; D057705:Transendothelial and Transepithelial Migration; D025521:Tumor Suppressor Proteins / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1