ER Stress and the UPR in Shaping Intestinal Tissue Homeostasis and Immunity

Abstract

An imbalance in the correct protein folding milieu of the endoplasmic reticulum (ER) can cause ER stress, which leads to the activation of the unfolded protein response (UPR). The UPR constitutes a highly conserved and intricately regulated group of pathways that serve to restore ER homeostasis through adaptation or apoptosis. Numerous studies over the last decade have shown that the UPR plays a critical role in shaping immunity and inflammation, resulting in the recognition of the UPR as a key player in pathological processes including complex inflammatory, autoimmune and neoplastic diseases. The intestinal epithelium, with its many highly secretory cells, forms an important barrier and messenger between the luminal environment and the host immune system. It is not surprising, that numerous studies have associated ER stress and the UPR with intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this review, we discuss our current understanding of the roles of ER stress and the UPR in shaping immune responses and maintaining tissue homeostasis. Furthermore, the role played by the UPR in disease, with emphasis on IBD and CRC, is described here. As a key player in immunity and inflammation, the UPR has been increasingly recognized as an important pharmacological target in the development of therapeutic strategies for immune-mediated pathologies. We summarize available strategies targeting the UPR and their therapeutic implications. Understanding the balance between homeostasis and pathophysiology, as well as means of manipulating this balance, provides an important avenue for future research.

Beyond the cell factory: Homeostatic regulation of and by the UPR ER

“…ER stress is commonly found in inflammatory diseases, such as diabetes, atherosclerosis, and inflammatory bowel disease ( 92 ). Accumulating evidence links the activation of the UPR ER in inflammatory signaling cascades, including the activation of cytokine release ( 93 ).…”

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

“…Recent studies have shown that cellular stress signaling, including endoplasmic reticulum (ER) stress signaling and the unfolded protein response (UPR), is linked to the normal function of multiple epithelial cell populations in the gut [ 16 , 17 ]. Accordingly, uncontrolled ER stress impairs mucosal barrier function, dysregulating the innate or adaptive immune response of the host cells and modulating the intestinal microbiota, which are established pathological conditions in IBD [ 16 , 17 , 18 , 19 ]. In fact, ER stress is associated with susceptibility to IBD, and signs of ER stress are commonly found in the ileal and colonic epithelia of patients with active IBD [ 17 , 20 ].…”

Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union

“…Chronic inflammation is one of the hallmark features of IBD, identical to a 'wildfire' that if uncontrolled causes collateral damage. There is also growing evidence that deregulated ER stress and UPR signaling pathways can instigate or magnify the inflammatory response in IBD (103)(104)(105)(106). Therefore, restoring a robust ER stress and UPR mechanism could be a potential therapeutic target.…”