The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis

Steven J McElroy; Shannon L Castle; Jessica K Bernard; Dana Almohazey; Catherine J Hunter; Brandon A Bell; Denise Al Alam; Larry Wang; Henri R Ford; Mark R Frey

doi:10.1016/j.ajpath.2014.06.015

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The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis

Journal article

Open access

Peer reviewed

The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis

Steven J McElroy, Shannon L Castle, Jessica K Bernard, Dana Almohazey, Catherine J Hunter, Brandon A Bell, Denise Al Alam, Larry Wang, Henri R Ford and Mark R Frey

The American journal of pathology, Vol.184(10), pp.2768-2778

10/2014

DOI: 10.1016/j.ajpath.2014.06.015

PMCID: PMC4715213

PMID: 25216938

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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.

Signal Transduction

Animals, Newborn

Paneth Cells - metabolism

Receptor, ErbB-4 - metabolism

Epithelial Cells - metabolism

Intestines - pathology

Cytokines - metabolism

Enterocolitis, Necrotizing - prevention & control

Enterocolitis, Necrotizing - metabolism

Humans

Ileum - metabolism

Rats

Milk, Human - chemistry

Rats, Sprague-Dawley

Animals

Female

Mice

Neuregulins - metabolism

Disease Models, Animal

Details

Title: Subtitle: The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis
Creators: Steven J McElroy - Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa
Shannon L Castle - Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California
Jessica K Bernard - 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
Dana Almohazey - 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
Catherine J Hunter - Departments of Surgery and Pediatrics, Ann and Robert H. Lurie Children's Hospital, Northwestern University, Chicago, Illinois
Brandon A Bell - Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California
Denise Al Alam - Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California
Larry Wang - Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California
Henri R Ford - Division of Pediatric Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California
Mark R Frey - 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
Resource Type: Journal article
Publication Details: The American journal of pathology, Vol.184(10), pp.2768-2778
DOI: 10.1016/j.ajpath.2014.06.015
PMID: 25216938
PMCID: PMC4715213
ISSN: 0002-9440
eISSN: 1525-2191
Grant note: R03DK090295 / NIDDK NIH HHS K01DK077956 / NIDDK NIH HHS R01AI014032 / NIAID NIH HHS R03DK097335 / NIDDK NIH HHS K01 DK077956 / NIDDK NIH HHS K08DK083677 / NIDDK NIH HHS K08 DK083677 / NIDDK NIH HHS R01 AI014032 / NIAID NIH HHS R01DK095004 / NIDDK NIH HHS R03 DK097335 / NIDDK NIH HHS R03 DK090295 / NIDDK NIH HHS R01 DK095004 / NIDDK NIH HHS L40 DK084865 / NIDDK NIH HHS
Language: English
Date published: 10/2014
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics
Record Identifier: 9984093222802771

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