TY - JOUR
T1 - The ErbB4 Ligand Neuregulin-4 Protects against Experimental Necrotizing Enterocolitis
AU - McElroy, Steven J.
AU - Castle, Shannon L.
AU - Bernard, Jessica K.
AU - Almohazey, Dana
AU - Hunter, Catherine J.
AU - Bell, Brandon A.
AU - Alam, Denise Al
AU - Wang, Larry
AU - Ford, Henri R.
AU - Freyz, Mark R.
N1 - Publisher Copyright:
Copyright © 2014 American Society for Investigative Pathology.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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 ablationeinduced 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 muytjensiieinduced 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.
AB - 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 ablationeinduced 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 muytjensiieinduced 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.
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U2 - 10.1016/j.ajpath.2014.06.015
DO - 10.1016/j.ajpath.2014.06.015
M3 - Article
C2 - 25216938
AN - SCOPUS:84922454995
VL - 184
SP - 2768
EP - 2778
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 10
ER -