The unfolded protein response and gastrointestinal disease

Abstract

As the inner lining of the gastrointestinal tract, the intestinal epithelium serves an essential role in innate immune function at the interface between the host and microbiota. Given the unique environmental challenges and thus physiologic secretory functions of this surface, it is exquisitely sensitive to perturbations that affect its capacity to resolve endoplasmic reticulum (ER) stress. Genetic deletion of factors involved in the unfolded protein response (UPR), which functions in the resolution of ER stress that arises from misfolded proteins, result in spontaneous intestinal inflammation closely mimicking human inflammatory bowel disease (IBD). This is demonstrated by observations wherein deletion of genes such as Xbp1 and Agr2 profoundly affects the intestinal epithelium and results in spontaneous intestinal inflammation. Moreover, both genes, along with others (e.g. ORDML3) represent genetic risk factors for human IBD, both Crohn’s disease and ulcerative colitis. Here we review the current mechanistic understanding for how unresolved ER stress can lead to intestinal inflammation, and highlight the findings that implicate ER stress as a genetically affected biological pathway in IBD. We further discuss environmental and microbial factors that might impact on the epithelium’s capacity to resolve ER stress, and which may constitute exogenous factors that may precipitate disease in genetically susceptible individuals.

Toll-like Receptor 4-mediated Endoplasmic Reticulum Stress in Intestinal Crypts Induces Necrotizing Enterocolitis

“…The current findings extend our knowledge regarding the role of ER stress in the development of intestinal inflammation, which until now has been thought to represent a protective strategy that exists in highly secretory cells of the intestinal epithelium including paneth and goblet cells (14). We also now identify a critical role for TLR4-induced ER stress within the intestinal stem cells, which has not been examined previously.…”

“…To determine whether the increase in ER stress was required for the induction in apoptosis in IEC-6 cells and intestinal crypts in response to TLR4 activation, we next treated cells or mice with LPS after selective knockdown or deletion of each of the key gene constituents of the ER stress signaling pathway (i.e., ATF6 (activating-transcription factor 6), XBP1 (X-box-binding protein 1) and PERK (protein kinase-related-PKR-like ER kinase) (14)). To knock down these ER stress genes, IEC-6 cells or wildtype mice were treated with lentivirus containing shRNA for the indicated gene or scrambled shRNA as described under "Experimental Procedures"; assessment by RT-PCR demonstrated highly efficient knockdown of the indicated ER stress gene in cells or mice treated with shRNA to the gene of interest, whereas treatment with scrambled shRNA had no effect as shown in Fig.…”

TFF2, a MUC6-binding lectin stabilizing the gastric mucus barrier and more (Review)

“…Generally, folding and initial polymerization of mucins occur in the ER, which requires the protein disulfide isomerase AGR2 (109,110). AGR2 has been reported to be involved in ER stress and the unfolded protein response (111). Of note, AGR2 Figure 3.…”

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

“…A large number of ER stress review articles focusing on cancer [16][17][18][19][20][21][22][23][24]; Alzheimer disease [25][26][27][28][29]; Parkinson [30,31], kidney [32][33][34], lung [35][36][37], cardiovascular [38][39][40][41][42], and inflammatory diseases [43][44][45][46][47]; obesity [48][49][50]; gastrointestinal disease [51]; and diabetes [50,[52][53][54][55][56][57][58][59][60] have recently been published. In addition, relationships between ER stress and environmental toxicants have also been summarized [61,62].…”