title: The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis.
abstract: Necrotizing enterocolitis (NEC) affects up to 10% of premature infants, has a mortality of 30%, and can leave surviving patients with significant morbidity. Neuregulin-4 (NRG4) is an ErbB4-specific ligand that promotes epithelial cell survival. Thus, this pathway could be protective in diseases such as NEC, in which epithelial cell death is a major pathologic feature. We sought to determine whether NRG4-ErbB4 signaling is protective in experimental NEC. NRG4 was used i) in the newborn rat formula feeding/hypoxia model; ii) in a recently developed model in which 14- to 16-day-old mice are injected with dithizone to induce Paneth cell loss, followed by Klebsiella pneumoniae infection to induce intestinal injury; and iii) in bacterially infected IEC-6 cells in vitro. NRG4 reduced NEC incidence and severity in the formula feed/hypoxia rat model. It also reduced Paneth cell ablation-induced NEC and prevented dithizone-induced Paneth cell loss in mice. In vitro, cultured ErbB4(-/-) ileal epithelial enteroids had reduced Paneth cell markers and were highly sensitive to inflammatory cytokines. Furthermore, NRG4 blocked, through a Src-dependent pathway, Cronobacter muytjensii-induced IEC-6 cell apoptosis. The potential clinical relevance of these findings was demonstrated by the observation that NRG4 and its receptor ErbB4 are present in human breast milk and developing human intestine, respectively. Thus, NRG4-ErbB4 signaling may be a novel pathway for therapeutic intervention or prevention in NEC.
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: McElroy
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Castle
authors.affiliation: Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Bernard
authors.affiliation: Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Dana
authors.initials: D
authors.lastname: Almohazey
authors.affiliation: Departments of Surgery and Pediatrics, Ann and Robert H. Lurie Children's Hospital, Northwestern University, Chicago, Illinois.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Hunter
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Bell
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Denise
authors.initials: D
authors.lastname: Al Alam
authors.affiliation: Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Larry
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Henri R
authors.initials: HR
authors.lastname: Ford
authors.affiliation: Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, California; Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California. Electronic address: mfrey@chla.usc.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Frey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000378:metabolism / Q000517:prevention & control*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D051379:Mice; D008895:Milk, Human / Q000737:chemistry*; D020880:Neuregulins / Q000378:metabolism*; D019879:Paneth Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D020880:Neuregulins; C467747:neuregulin-4; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4