Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union

Abstract

The intestinal tract encompasses the largest mucosal surface fortified with a fine layer of intestinal epithelial cells along with highly sophisticated network of the lamina propria immune cells that are indispensable to sustain gut homeostasis. However, it can be challenging to uphold homeostasis when these cells in the intestine are perpetually exposed to insults of both endogenous and exogenous origin. The complex networking and dynamic microenvironment in the intestine demand highly functional cells ultimately burdening the endoplasmic reticulum (ER) leading to ER stress. Unresolved ER stress is one of the primary contributors to the pathogenesis of inflammatory bowel diseases (IBD). Studies also suggest that ER stress can be the primary cause of inflammation and/or the consequence of inflammation. Therefore, understanding the patterns of expression of ER stress regulators and deciphering the intricate interplay between ER stress and inflammatory pathways in intestinal epithelial cells in association with lamina propria immune cells contribute toward the development of novel therapies to tackle IBD. This review provides imperative insights into the molecular markers involved in the pathogenesis of IBD by potentiating ER stress and inflammation and briefly describes the potential pharmacological intervention strategies to mitigate ER stress and IBD. In addition, genetic mutations in the biomarkers contributing to abnormalities in the ER stress signaling pathways further emphasizes the relevance of biomarkers in potential treatment for IBD.

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

“…Unresolvable ER stress leads to inflammatory responses (Eugene et al, 2020) and inflammation is another pathological feature of L-arginine-induced AP (El Morsy and Ahmed, 2020; Abdelzaher ,B, immunohistochemical staining of F4/80 and CD11b showed that there was a large amount of macrophage infiltration in the pancreatic tissue of L-arginine treated mice, and intraperitoneal injection of 20 μg/kg-MFG-E8 effectively reduced the degree of macrophage infiltration (p < 0.05). Gr1 and MPO-labeled neutrophils showed the same trend as macrophages, suggesting that exogenous MFG-E8 effectively reduced the number of inflammatory cells in the pancreatic tissue (p < 0.05, Figures 3A,B).…”

Tissue Damage, Not Infection, Triggers Hepatic Unfolded Protein Response in an Experimental Rat Peritonitis Model

“…However, we did not analyze the local effects of peritonitis. Several studies have already highlighted the relevance of intestinal ER stress in peritonitis that is tightly linked to deranged intestinal tissue homeostasis and immunity ( 51 , 52 ), and particularly the impairment of the intestinal barrier function ( 53 ). Further studies will be necessary to clarify the source or the nature of the compounds that trigger the ER stress/UPR and inflammatory response in the liver.…”

Endoplasmic Reticulum Stress Disturbs Lipid Homeostasis and Augments Inflammation in the Intestine and Isolated Intestinal Cells of Large Yellow Croaker (Larimichthys crocea)

“…Continual exposure to dietary metabolites, toxins impeded, exogenous antigens, and gut microflora makes the intestine susceptible to invasion by exogenous stress, ultimately burdening the ER resulting in ER stress ( 45 ). Unresolved ER stress can be the primary cause of inflammation in the intestine ( 46 , 47 ).…”