title: Enteric neuronal density contributes to the severity of intestinal inflammation.
abstract: OBJECTIVE
  Enteric neurons have been reported to be increased in inflamed regions of the bowel in patients with inflammatory bowel disease or intestinal neurogangliomatosis. It is impossible to determine whether this hyperinnervation predates intestinal inflammation, results from it, or contributes to its severity in humans, so we studied this process in mice.
  
  
  METHODS
  To determine whether the density of enteric neurons determines the severity of inflammation, we studied transgenic mice that have greater than normal (NSE-noggin mice, which overexpress noggin under the control of the neuron-specific enolase promoter) or fewer than normal (Hand2(+/-) mice) numbers of neurons in the enteric nervous system. Colitis was induced with trinitrobenzene sulfonic acid or dextran sulfate sodium, and the intensity of the resulting inflammation in Hand2(+/-) and NSE-noggin mice was compared with that of wild-type littermates.
  
  
  RESULTS
  Severity of each form of colitis (based on survival, symptom, and histologic scores; intestinal expression of genes that encode proinflammatory molecules; and levels of neutrophil elastase and p50 nuclear factor κB) were significantly reduced in Hand2(+/-) mice and significantly increased in NSE-noggin animals. Neither mouse differed from wild-type in the severity of delayed-type hypersensitivity (edema, T-cell and neutrophil infiltration, or expression of interleukin-1β, interferon-γ, or tumor necrosis factor-α) induced in the ears using 2,4-dinitro-1-fluorobenzene. Transgene effects on inflammation were therefore restricted to the gastrointestinal tract.
  
  
  CONCLUSIONS
  The severity of intestinal inflammation is associated with the density of the enteric innervation in mice. Abnormalities in development of the enteric nervous system might therefore contribute to the pathogenesis of inflammatory bowel disease.
authors.affiliation: Department of Pediatrics, Morgan Stanley Children's Hospital, New York, New York 10032, USA. kjg2133@columbia.edu
authors.forename: Kara Gross
authors.initials: KG
authors.lastname: Margolis
authors.forename: Korey
authors.initials: K
authors.lastname: Stevanovic
authors.forename: Nima
authors.initials: N
authors.lastname: Karamooz
authors.forename: Zi Shan
authors.initials: ZS
authors.lastname: Li
authors.forename: Ankur
authors.initials: A
authors.lastname: Ahuja
authors.forename: Fabien
authors.initials: F
authors.lastname: D'Autréaux
authors.forename: Virginia
authors.initials: V
authors.lastname: Saurman
authors.forename: Alcmene
authors.initials: A
authors.lastname: Chalazonitis
authors.forename: Michael David
authors.initials: MD
authors.lastname: Gershon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate; D004139:Dinitrofluorobenzene; D017615:Enteric Nervous System / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000378:metabolism; D012720:Severity of Illness Index; D013534:Survival; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D016264:Dextran Sulfate; D004139:Dinitrofluorobenzene; D007371:Interferon-gamma; D053583:Interleukin-1beta; D019272:Leukocyte Elastase; D052002:NF-kappa B p50 Subunit; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha; D000099176:Noggin Protein; C498766:Hand2 protein, mouse