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. 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. Necrotizing enterocolitis (NEC) is a devastating intestinal disease primarily affecting premature infants. In the United States, NEC afflicts 7% of infants weighing <1500 g.1Hunter C.J. Upperman J.S. Ford H.R. Camerini V. Understanding the susceptibility of the premature infant to necrotizing enterocolitis (NEC).Pediatr Res. 2008; 63: 117-123Crossref PubMed Scopus (185) Google Scholar In addition to prematurity, risk factors include hypoxia, bacterial colonization of the intestine, and formula feeding.2Emami C.N. Petrosyan M. Giuliani S. Williams M. Hunter C. Prasadarao N.V. Ford H.R. Role of the host defense system and intestinal microbial flora in the pathogenesis of necrotizing enterocolitis.Surg Infect (Larchmt). 2009; 10: 407-417Crossref PubMed Scopus (53) Google Scholar The development of NEC seems to be multifactorial, and patients may have any combination of risk factors at the time of presentation. The current disease model is that the immature gut barrier, along with defects in endogenous antimicrobial activity,3McElroy S.J. Underwood M.A. Sherman M.P. Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis.Neonatology. 2013; 103: 10-20Crossref PubMed Scopus (70) Google Scholar allows bacterial translocation across the epithelium, triggering an inflammatory response that further worsens gut barrier function. Pathogenic bacteria,4Hunter C.J. Petrosyan M. Ford H.R. Prasadarao N.V. 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Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar Thus, seems that ErbB4 is a response to the than of disease and that ErbB4 with ligand is protective the role of this signaling pathway in the intestine, or has been We that ErbB4 and its have a protective role in the in the of injury and of ErbB4 in intestinal and the hypothesis that NRG4-ErbB4 signaling is protective in experimental NEC. the animal all the studies were and by the and and of or the of as and were in with the in the for the and of for the of the for the and of Research for the and of Google Scholar the study of human the on for of and the and the of study and the of were in the and potential by were in were a study and were to this at milk the study risk and was was at the time of to the and of were in the was milk were with the date of and were in human NEC and were human were infants at the and H. were were for the of this and study The of the for and the were The intestinal were of NEC for and a of NEC with a of NEC to of such as NEC or a of NEC current disease was and and or in and at for NEC was in newborn by formula feeding/hypoxia as A. Boyle P. D. S.C. Ford H.R. of and in experimental necrotizing enterocolitis.J Res. Full Text PDF PubMed Scopus Google Scholar at were the of treatment i) with and ii) by of of formula of of in of milk with with and and with of NRG4 in a formula for ErbB4 as by a of to followed by for on ileal to the or iii) as ii) with an of of NRG4 to were and were of were were was and and in the intestinal were by a to to on pathologic epithelial intestinal epithelial and mice to were their and in a and the and were to an experimental NEC as C. Sherman M.P. D. S.J. Paneth cell in the of Klebsiella pneumoniae necrotizing enterocolitis injury in the of immature PubMed Scopus Google Scholar were of the dithizone or an of as by Paneth which are highly sensitive to M. 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Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar apoptosis in IEC-6 cells was by a to with a S.J. Underwood M.A. Sherman M.P. Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis.Neonatology. 2013; 103: 10-20Crossref PubMed Scopus (70) Google Scholar were a as V. Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar a was used to approximately in IEC-6 were was and was IEC-6 were for and were with factors for were with for the of and were of cells was a The used were and and and were and NRG4 was Breast milk was was in and at were and at for to the The were and in for were by of the or as ErbB4 is by injury and in the D. The ErbB4 factor receptor is for epithelial cell in the of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar as a response to and NRG4 apoptosis in the V. Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar whether ErbB4 is protective in the developing intestine, used the model of rat NEC. In this highly J. factor intestinal apoptosis in neonatal with necrotizing enterocolitis.J Pediatr Surg. 2006; (discussion Full Text Full Text PDF PubMed Scopus Google Scholar, A. Boyle P. D. S.C. Ford H.R. of and in experimental necrotizing enterocolitis.J Res. Full Text PDF PubMed Scopus Google Scholar the combination of formula feeding with a clinical and to human NEC. had epithelial NRG4 to ErbB4 had to of a significant protective with of in and in the had a reduced incidence of as the of with at on in versus in The of cells in the epithelial was also reduced in development may be the as in also whether ErbB4 in experimental NEC. for ErbB4 an in receptor in versus NRG4-ErbB4 signaling in a model of NEC, used the recently C. Sherman M.P. D. S.J. Paneth cell in the of Klebsiella pneumoniae necrotizing enterocolitis injury in the of immature PubMed Scopus Google Scholar in mice. In this Paneth cells are by dithizone by Paneth followed by pneumoniae in NEC-like NRG4 by with dithizone was protective in this in mice versus in NRG4 to the rat injury in the mice was associated with ErbB4 In the model of NEC, dithizone the Paneth cell the to NEC has been associated with loss of Paneth cells in the S.J. Underwood M.A. Sherman M.P. Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis.Neonatology. 2013; 103: 10-20Crossref PubMed Scopus (70) Google Scholar that this of the model may be for the development of clinical whether ErbB4 signaling is affecting the Paneth cell or mice with or by for to identify and Paneth NRG4 Paneth cell loss in the model Paneth cells that of this or of Paneth cell may be of the of NEC. further the role of ErbB4 in Paneth cell and intestinal epithelial used ileal epithelial T. M. A. P. P.J. H. cells in a 2009; PubMed Scopus Google Scholar mice with ErbB4 in their intestinal In these mice have an intestinal to factor H. Y. of a soluble intestinal in mice through an PubMed Scopus Google Scholar and Y. and by epithelial cell PubMed Scopus Google Scholar The of may be to used the model to epithelial with enteroids a significant in the Paneth cell and a The loss of in enteroids was with that in enteroids to an inflammatory in the pathogenesis of M.S. Hsueh W. Necrotizing enterocolitis: role of platelet activating factor, endotoxin, and tumor necrosis factor.J Pediatr. 1990; 117: S47-S51Abstract Full Text PDF PubMed Scopus (76) Google Scholar, 7Halpern M.D. Clark J.A. Saunders T.A. Doelle S.M. Hosseini D.M. Stagner A.M. Dvorak B. Reduction of experimental necrotizing enterocolitis with anti-TNF-alpha.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G757-G764Crossref PubMed Scopus (76) Google Scholar Furthermore, enteroids were to with the a loss of with surviving epithelial cells at in the signaling in NRG4 of the intestine, infected IEC-6 rat ileal epithelial cells with C. a to associated with NEC. C. has been used with IEC-6 cells to study cell C.J. Singamsetty V.K. Chokshi N.K. Boyle P. Camerini V. Grishin A.V. Upperman J.S. Ford H.R. Prasadarao N.V. Enterobacter sakazakii enhances epithelial cell injury by inducing apoptosis in a rat model of necrotizing enterocolitis.J Infect Dis. 2008; 198: 586-593Crossref PubMed Scopus (87) Google Scholar were to C. in the of or the factors or NRG4 apoptosis was by a for and to C. apoptosis in IEC-6 cells in receptor apoptosis with versus and NRG4 had effect on C. of IEC-6 cell in a infection reduced IEC-6 cell and NRG4 was to this NRG4 also induce IEC-6 Thus, NRG4 signaling is for in this cell model. to ErbB4 has a of potential for signaling A. A. J. G. of ErbB4 of that are in their 2008; Full Text Full Text PDF PubMed Scopus Google Scholar of the is with this has been associated with signaling in the T. H. 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The ErbB4 receptor is expressed in the W.J. of the and in human and and in a of PubMed Scopus Google Scholar to date its has been that an ErbB4-specific is protective in experimental NEC. We in and Furthermore, ErbB4 is for of the Paneth cell and epithelial in and NRG4 bacterially apoptosis in the intestinal IEC-6 cell through a Src-dependent pathway with the observation that NRG4 is present in human milk these that ErbB4 signaling has a role in of the developing inflammatory that NRG4 is intestinal the that endogenous of this factor are reduced in a model of intestinal Y. epithelial cell and apoptosis in a model of J Physiol Gastrointest Liver Physiol. PubMed Scopus (53) Google Scholar loss of NRG4 in human inflammatory disease and in the model of V. Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar Thus, is that the inflammatory in NEC may endogenous of have that human breast milk NRG4 formula is that the immature neonatal has a low of at and an that of formula with NRG4 intestinal is with breast milk of NRG4 to the immature Thus, infants is a risk factor for development of be in that in the present study were to milk of infants that is whether NRG4 of in milk these in milk expressed by of preterm infants. a study the in in preterm factor and in human milk premature Physiol. Google Scholar the of for infants at risk for such as NEC. these that in factor can have an effect on the of the developing and study is on the and factors in such as NEC or inflammatory In addition to NRG4 in human breast also of its in neonatal human infants or recently NEC that of these was to determine whether ErbB4 is present in neonatal and NEC. We are with the used in this to the of receptor in of these is to that ErbB4 is present in the intestinal of human and that this that of ErbB4 is to human The of this receptor in NEC and is the of in The in this study are with on the in which receptor and their have been as of and response to V. Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar, D. The ErbB4 factor receptor is for epithelial cell in the of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, T. H. W. of receptor and intestinal epithelial cells A. 2008; PubMed Scopus (87) Google Scholar, T. factor receptor epithelial cell and J Physiol Gastrointest Liver Physiol. PubMed Scopus Google Scholar We demonstrated that ErbB4 is that its apoptosis in cultured D. The ErbB4 factor receptor is for epithelial cell in the of 2009; Full Text Full Text PDF PubMed Scopus Google Scholar and that NRG4 the in cell death by a V. 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R.J. of the factor receptor in epithelial cells by of PubMed Scopus Google Scholar Thus, may be that NRG4-ErbB4 signaling is an for the treatment of NEC or inflammatory of the in that its to the that have been as for in the and are of and is that a combination of molecules at and NRG4 to and NEC. NEC in premature infants is associated with a loss of Paneth S.J. Underwood M.A. Sherman M.P. Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis.Neonatology. 2013; 103: 10-20Crossref PubMed Scopus (70) Google Scholar, G. D. of in the intestinal Paneth cells of newborn infants with necrotising enterocolitis.J PubMed Scopus (70) Google Scholar Paneth cell in premature infants are than in A. S. A. in necrotizing Res. PubMed Scopus Google Scholar are present by of A. R.J. and PubMed Scopus Google Scholar the time at which infants J. Necrotizing J PubMed Scopus Google Scholar, W. Neonatal and of of necrotizing enterocolitis in preterm PubMed Scopus Google Scholar The that NRG4 the Paneth cell in mice to NEC and ErbB4 Paneth cell in cultured ileal enteroids Thus, of this may be of the for the on injury in NEC. that the be the potential effect on human to a in ErbB4 in NEC. It is that ligand to formula feeding or intestinal V. Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar, Y. epithelial cell and apoptosis in a model of J Physiol Gastrointest Liver Physiol. PubMed Scopus (53) Google has a than receptor in the model. ErbB4 in the enteroids had approximately the on Paneth cells and epithelial as the signaling ligand in the disease and seems to In NRG4 has in as in and in V. Neuregulin-4 is a factor for epithelial cells in and in PubMed Scopus Google Scholar It is to to Paneth cell may the rat model to these cells are present in newborn Yu J. A. 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M. with and as a for the of that to the PubMed Scopus Google Scholar and in in the intestinal T. Fuchs S. C.J. of intestinal cell and the response by 2013; PubMed Scopus Google Scholar are currently in the It may be that in signaling and are for the to NRG4-ErbB4 signaling in cell NEC is a highly disease that can to intestinal gut and in the factor signaling that the developing could to for or this devastating In this the of ErbB4 by NRG4 in in NEC with pathologic and an in model that has demonstrated relevance to the of the C.J. Singamsetty V.K. Chokshi N.K. Boyle P. Camerini V. Grishin A.V. Upperman J.S. Ford H.R. Prasadarao N.V. Enterobacter sakazakii enhances epithelial cell injury by inducing apoptosis in a rat model of necrotizing enterocolitis.J Infect Dis. 2008; 198: 586-593Crossref PubMed Scopus (87) Google Scholar, C.J. Williams M. Petrosyan M. Y. D. Upperman J.S. Ford H.R. Prasadarao N.V. intestinal epithelial cell injury by Enterobacter in and in the newborn rat model of necrotizing 2009; PubMed Scopus Google Scholar is beneficial model can all of the human We that NRG4 was protective in model. Furthermore, NRG4 is present in human milk and is to formula as a these the that ErbB4 be a therapeutic for NEC and intestinal diseases epithelial cell We the of The Research for and for and and and the and the and the and and the