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Pediatric Surgery International
Published in: Pediatric Surgery International 9/2021

01-09-2021 | Review Article

Endoplasmic reticulum stress in the acute intestinal epithelial injury of necrotizing enterocolitis

Authors: Ethan Lau, Carol Lee, Bo Li, Agostino Pierro

Published in: Pediatric Surgery International | Issue 9/2021

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Abstract

Endoplasmic reticulum (ER) is a dynamic organelle that has many functions including protein synthesis, lipid synthesis, and calcium metabolism. Any perturbation in the ER such as accumulation of unfolded or misfolded proteins in the ER lumen causes ER stress. ER stress has been implicated in many intestinal inflammatory diseases. However, the role of ER stress in acute intestinal epithelial injuries such as necrotizing enterocolitis in preterm neonates, remains incompletely understood. In this review, we introduce ER structure, functions and summarize the intracellular signaling pathways involved in unfolded protein response (UPR), a survival mechanism in which cells exert an adaptive function to restore homeostasis in the ER. However, intense and prolonged ER stress induces apoptotic response which results in apoptotic cell death. We also discuss and highlight recent advances that have improved our understanding of the molecular mechanisms that regulate the ER stress in acute intestinal epithelial injuries such as necrotizing enterocolitis (NEC). We focus on the role of ER stress in influencing gut homeostasis in the neonatal period and on the potential therapeutic interventions to alleviate ER stress-induced cell death in NEC.
Literature
1.
2.
Kato A et al (2019) Recurrent short-term hypoglycemia and hyperglycemia induce apoptosis and oxidative stress via the ER stress response in immortalized adult mouse Schwann (IMS32) cells. Neurosci Res 147:26–32PubMedCrossRef
3.
Hall NJ et al (2004) Hyperglycemia is associated with increased morbidity and mortality rates in neonates with necrotizing enterocolitis. J Pediatr Surg 39(6):898–901PubMedCrossRef
4.
Csala M et al (2012) The endoplasmic reticulum as the extracellular space inside the cell: role in protein folding and glycosylation. Antioxid Redox Signal 16(10):1100–1108PubMedCrossRef
5.
Hagiwara M, Nagata K (2012) Redox-dependent protein quality control in the endoplasmic reticulum: folding to degradation. Antioxid Redox Signal 16(10):1119–1128PubMedCrossRef
6.
7.
Krebs J, Groenendyk J, Michalak M (2011) Ca2+-signaling, alternative splicing and endoplasmic reticulum stress responses. Neurochem Res 36(7):1198–1211PubMedCrossRef
8.
9.
Dohrman A et al (1998) Mucin gene (MUC 2 and MUC 5AC) upregulation by gram-positive and gram-negative bacteria. Biochim Biophys Acta 1406(3):251–259PubMedCrossRef
10.
Romero-Brey I, Bartenschlager R (2016) Endoplasmic reticulum: the favorite intracellular niche for viral replication and assembly. Viruses 8(6):160PubMedCentralCrossRef
11.
von dem Bussche A et al (2010) Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication. J Hepatol 53(5):797–804CrossRef
12.
Afrazi A et al (2014) Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis. J Biol Chem 289(14):9584–9599PubMedPubMedCentralCrossRef
13.
Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086PubMedCrossRef
14.
Mateus D et al (2018) Rab7a modulates ER stress and ER morphology. Biochim Biophys Acta Mol Cell Res 1865(5):781–793PubMedCrossRef
15.
Kim SK et al (2015) Palmitate induces cisternal ER expansion via the activation of XBP-1/CCTα-mediated phospholipid accumulation in RAW 2647 cells. Lipids Health Dis 14:73PubMedPubMedCentralCrossRef
16.
Schuck S et al (2009) Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J Cell Biol 187(4):525–536PubMedPubMedCentralCrossRef
17.
18.
Huang G et al (2006) ER stress disrupts Ca2+-signaling complexes and Ca2+ regulation in secretory and muscle cells from PERK-knockout mice. J Cell Sci 119(Pt 1):153–161PubMedCrossRef
19.
Shen J et al (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3(1):99–111PubMedCrossRef
20.
Lee AS (2005) The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 35(4):373–381PubMedCrossRef
21.
22.
Yoshida H et al (2006) pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. J Cell Biol 172(4):565–575PubMedPubMedCentralCrossRef
23.
Yoshida H et al (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107(7):881–891PubMedCrossRef
24.
Khan MF, Spurgeon S, von der Haar T (2018) Origins of robustness in translational control via eukaryotic translation initiation factor (eIF) 2. J Theor Biol 445:92–102PubMedCrossRef
25.
Meng X et al (2018) Periostin has a protective role in melatonin-induced cell apoptosis by inhibiting the eIF2α-ATF4 pathway in human osteoblasts. Int J Mol Med 41(2):1003–1012PubMed
26.
Haze K et al (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10(11):3787–3799PubMedPubMedCentralCrossRef
27.
Chotikatum S, Naim HY, El-Najjar N (2018) Inflammation induced ER stress affects absorptive intestinal epithelial cells function and integrity. Int Immunopharmacol 55:336–344PubMedCrossRef
28.
Heazlewood CK et al (2008) Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 5(3):e54PubMedPubMedCentralCrossRef
29.
Li B et al (2019) Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis. PLoS ONE 14(1):e0211431PubMedPubMedCentralCrossRef
30.
Wu RY et al (2019) Human milk oligosaccharides increase mucin expression in experimental necrotizing enterocolitis. Mol Nutr Food Res 63(3):e1800658PubMed
31.
Hu H et al (2018) The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol 9:3083PubMedCrossRef
32.
Yamaguchi H, Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279(44):45495–45502PubMedCrossRef
33.
Lu P et al (2013) Endoplasmic reticulum stress, unfolded protein response and altered T cell differentiation in necrotizing enterocolitis. PLoS ONE 8(10):e78491PubMedPubMedCentralCrossRef
34.
Kaser A et al (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134(5):743–756PubMedPubMedCentralCrossRef
35.
Lee JY et al (2018) Molecular pathophysiology of epithelial barrier dysfunction in inflammatory bowel diseases. Proteomes 6(2):17PubMedCentralCrossRef
36.
Ravisankar S et al (2018) Necrotizing enterocolitis leads to disruption of tight junctions and increase in gut permeability in a mouse model. BMC Pediatr 18(1):372PubMedPubMedCentralCrossRef
37.
38.
Lodha A et al (2017) The role of interleukin-6 and interleukin-8 circulating cytokines in differentiating between feeding intolerance and necrotizing enterocolitis in preterm infants. Am J Perinatol 34(13):1286–1292PubMedCrossRef
39.
Hall NJ, Eaton S, Pierro A (2013) Royal australasia of surgeons guest lecture necrotizing enterocolitis: prevention, treatment, and outcome. J Pediatr Surg 48(12):2359–2367PubMedCrossRef
40.
Rees CM, Pierro A, Eaton S (2007) Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed 92(3):F193–F198PubMedCrossRef
41.
Cotten CM et al (2005) Prolonged hospital stay for extremely premature infants: risk factors, center differences, and the impact of mortality on selecting a best-performing center. J Perinatol 25(10):650–655PubMedCrossRef
42.
Chen Y et al (2016) The role of ischemia in necrotizing enterocolitis. J Pediatr Surg 51(8):1255–1261PubMedCrossRef
43.
Chen Y, et al. (2019) Formula feeding and immature gut microcirculation promote intestinal hypoxia, leading to necrotizing enterocolitis. Dis Model Mech 12(12):1–10
44.
Thompson AM, Bizzarro MJ (2008) Necrotizing enterocolitis in newborns: pathogenesis, prevention and management. Drugs 68(9):1227–1238PubMedCrossRef
45.
Li P et al (2019) TUDCA attenuates intestinal injury and inhibits endoplasmic reticulum stress-mediated intestinal cell apoptosis in necrotizing enterocolitis. Int Immunopharmacol 74:105665PubMedCrossRef
46.
Simons BD, Clevers H (2011) Stem cell self-renewal in intestinal crypt. Exp Cell Res 317(19):2719–2724PubMedCrossRef
47.
Zhou Y et al (2017) Inflammation and apoptosis: dual mediator role for toll-like receptor 4 in the development of necrotizing enterocolitis. Inflamm Bowel Dis 23(1):44–56PubMedCrossRef
48.
Schaart MW et al (2009) Epithelial functions of the residual bowel after surgery for necrotising enterocolitis in human infants. J Pediatr Gastroenterol Nutr 49(1):31–41PubMedCrossRef
49.
van Gorp C et al (2021) Intestinal goblet cell loss during chorioamnionitis in fetal lambs: mechanistic insights and postnatal implications. Int J Mol Sci 22(4):1946PubMedPubMedCentralCrossRef
50.
Bergmann KR et al (2013) Bifidobacteria stabilize claudins at tight junctions and prevent intestinal barrier dysfunction in mouse necrotizing enterocolitis. Am J Pathol 182(5):1595–1606PubMedPubMedCentralCrossRef
51.
Li B et al (2021) Intestinal epithelial tight junctions and permeability can be rescued through the regulation of endoplasmic reticulum stress by amniotic fluid stem cells during necrotizing enterocolitis. Faseb J 35(1):e21265PubMed
52.
Nieto N et al (2002) Dietary polyunsaturated fatty acids improve histological and biochemical alterations in rats with experimental ulcerative colitis. J Nutr 132(1):11–19PubMedCrossRef
53.
Zhang Y et al (2011) α-Linolenic acid prevents endoplasmic reticulum stress-mediated apoptosis of stearic acid lipotoxicity on primary rat hepatocytes. Lipids Health Dis 10:81PubMedPubMedCentralCrossRef
54.
Caplan MS et al (2001) Effect of polyunsaturated fatty acid (PUFA) supplementation on intestinal inflammation and necrotizing enterocolitis (NEC) in a neonatal rat model. Pediatr Res 49(5):647–652PubMedCrossRef
55.
Nakagawa T et al (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403(6765):98–103PubMedCrossRef
56.
Zhu X et al (2020) Potential role of endoplasmic reticulum stress is involved in the protection of fish oil on neonatal rats with necrotizing enterocolitis. Sci Rep 10(1):6448PubMedPubMedCentralCrossRef
57.
58.
Berger E, Haller D (2011) Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells. Biochem Biophys Res Commun 409(4):610–615PubMedCrossRef
59.
Fu D et al (2019) β-arrestin-2 enhances intestinal epithelial apoptosis in necrotizing enterocolitis. Aging (Albany NY) 11(19):8294–8312CrossRef
60.
61.
Li B et al (2019) Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis. Cell Death Dis 10(10):743PubMedPubMedCentralCrossRef
62.
Li B et al (2014) Early maternal separation induces alterations of colonic epithelial permeability and morphology. Pediatr Surg Int 30(12):1217–1222PubMedCrossRef
63.
Li B et al (2016) Endoplasmic reticulum stress is involved in the colonic epithelium damage induced by maternal separation. J Pediatr Surg 51(6):1001–1004PubMedCrossRef
64.
Okazaki T et al (2014) Inhibition of the dephosphorylation of eukaryotic initiation factor 2α ameliorates murine experimental colitis. Digestion 90(3):167–178PubMedCrossRef
Metadata
Title
Endoplasmic reticulum stress in the acute intestinal epithelial injury of necrotizing enterocolitis
Authors
Ethan Lau
Carol Lee
Bo Li
Agostino Pierro
Publication date
01-09-2021
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Surgery International / Issue 9/2021
Print ISSN: 0179-0358
Electronic ISSN: 1437-9813
DOI
https://doi.org/10.1007/s00383-021-04929-8

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