Endoplasmic Reticulum Stress, Unfolded Protein Response and Altered T Cell Differentiation in Necrotizing Enterocolitis

Peng Lu,Johannes B Van Goudoever,Anita M Korteland-Van Male,Marie-Chantal Struijs,Adrianus C J M De Bruijn,Ingrid B Renes,Janneke Witte-Bouma,Jiaping Mei,Derya Unutmaz

doi:10.1371/journal.pone.0078491

Abstract

BackgroundEndoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) play important roles in chronic intestinal inflammation. Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants and is characterized by acute intestinal inflammation and necrosis. The objective of the study is to investigate the role of ER stress and the UPR in NEC patients.MethodsIleal tissues from NEC and control patients were obtained during surgical resection and/or at stoma closure. Splicing of XBP1 was detected using PCR, and gene expression was quantified using qPCR and Western blot.ResultsSplicing of XBP1 was only detected in a subset of acute NEC (A-NEC) patients, and not in NEC patients who had undergone reanastomosis (R-NEC). The other ER stress and the UPR pathways, PERK and ATF6, were not activated in NEC patients. A-NEC patients showing XBP1 splicing (A-NEC-XBP1s) had increased mucosal expression of GRP78, CHOP, IL6 and IL8. Similar results were obtained by inducing ER stress and the UPR in vitro. A-NEC-XBP1s patients showed altered T cell differentiation indicated by decreased mucosal expression of RORC, IL17A and FOXP3. A-NEC-XBP1s patients additionally showed more severe morphological damage and a worse surgical outcome. Compared with A-NEC patients, R-NEC patients showed lower mucosal IL6 and IL8 expression and higher mucosal FOXP3 expression.ConclusionsXBP1 splicing, ER stress and the UPR in NEC are associated with increased IL6 and IL8 expression levels, altered T cell differentiation and severe epithelial injury.

Highlights

Endoplasmic reticulum (ER) stress-related inflammation is involved in the pathogenesis of various chronic inflammatory diseases, including inflammatory bowel disease [1,2]
ER stress and the unfolded protein response (UPR) are involved in various chronic inflammatory diseases, including inflammatory bowel disease
Our data indicate that acute Necrotizing enterocolitis (NEC) patients with ER stress and activation of the UPR show increased interleukin 6 (IL6) and IL8 expression with altered T cell differentiation

Summary

Introduction

Endoplasmic reticulum (ER) stress-related inflammation is involved in the pathogenesis of various chronic inflammatory diseases, including inflammatory bowel disease [1,2]. To restore ER homeostasis, mammalian cells activate a process called unfolded protein response (UPR), which is marked by induction of a number of UPR-related genes including GRP78 and C/EBP homologous protein (CHOP). Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) play important roles in chronic intestinal inflammation. The other ER stress and the UPR pathways, PERK and ATF6, were not activated in NEC patients. A-NEC patients showing XBP1 splicing (A-NEC-XBP1s) had increased mucosal expression of GRP78, CHOP, IL6 and IL8. A-NEC-XBP1s patients showed altered T cell differentiation indicated by decreased mucosal expression of RORC, IL17A and FOXP3. Conclusions: XBP1 splicing, ER stress and the UPR in NEC are associated with increased IL6 and IL8 expression levels, altered T cell differentiation and severe epithelial injury

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