Potential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homologue in Crohn's Disease Fibrosis

Overview

Journal J Crohns Colitis

Publisher Oxford University Press

Date 2021 Apr 6

PMID 33822017

Citations 13

Authors

Sophie Vieujean

Shurong Hu

Emeline Bequet

Catherine Salee

Charlotte Massot

Noella Bletard

Nicolas Pierre

Florence Quesada Calvo

Dominique Baiwir

Gabriel Mazzucchelli

Edwin De Pauw

Carla Coimbra Marques

Philippe Delvenne

Florian Rieder

Edouard Louis

Marie-Alice Meuwis

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Intestinal fibrosis is a common complication of Crohn's disease [CD]. It is characterised by an accumulation of fibroblasts differentiating into myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined.

Methods: We performed a pilot proteomic study comparing the proteome of surface epithelium, isolated by laser-capture microdissection, in normal and fibrotic zones of resected ileal CD strictures [13 zones collected in five patients]. Proteins of interests were validated by immunohistochemistry [IHC] in ileal and colonic samples of stricturing CD [n = 44], pure inflammatory CD [n = 29], and control [n = 40] subjects. The pro-fibrotic role of one selected epithelial protein was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model.

Results: Proteomic study revealed an endoplasmic reticulum [ER] stress proteins increase in the epithelium of CD ileal fibrotic strictures, including anterior gradient protein 2 homologue [AGR2] and binding-immunoglobulin protein [BiP]. This was confirmed by IHC. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2 intracellular expression and its secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin, led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. By using recombinant protein and blocking agent for AGR2, we demonstrated that the secretion of this protein by epithelial cells can play a role in the myofibroblastic differentiation.

Conclusions: The development of CD fibrotic strictures could involve epithelial ER stress and particularly the secretion of AGR2.

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