Potential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homologue in Crohn's Disease Fibrosis. (2nd April 2021)

• Record Type: Journal Article
• Authors: Vieujean, Sophie; Hu, Shurong; Bequet, Emeline; Salee, Catherine; Massot, Charlotte; Bletard, Noëlla; Pierre, Nicolas; Quesada Calvo, Florence; Baiwir, Dominique; Mazzucchelli, Gabriel; De Pauw, Edwin; Coimbra Marques, Carla; Delvenne, Philippe; Rieder, Florian; Louis, Edouard; Meuwis, Marie-Alice
• Is Part Of: Journal of Crohn's and colitis. Volume 15:Number 10(2021)
• Page Start: 1737
• Page End: 1750
• Publication Date: 2021-04-02
• Subjects: CD fibrosis -- ER stress -- anterior gradient protein 2 homologue; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjab061
• Languages: English
• ISSNs: 1873-9946

Abstract

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.