The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Abstract

The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.Frontiers in Immunology | www.frontiersin.org Conflict of Interest: ZL serves as member of scientific advisory board for Alphamab and Henlius Biotech and has a sponsored research agreement with Bristol-Myers Squibb.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

“…Moreover, in the frontotemporal dementia disease, the high levels of p-PERK, p-eIF2α and ATF4 were reduced after orally treating transgenic mouse model with GSK2606414 [ 170 ]. Recently, it was found that this compound is a potential therapy of cancer since it inhibits KIT, a type III receptor tyrosine kinase (RTK), known to activate many signal transduction pathways including RAS/ERK (Extracellular Signal-Regulated Kinase), PI3K/AKT or PKB (Phosphoinositide 3-kinase/ Protein kinase B), phospholipase C, JAK/STAT (Janus kinase/signal transducers and activators of transcription), and Src kinase pathways [ 171 ]. However, it has been reported that GSK2606414 may cause side effects related to pancreatic toxicity [ 169 ] maybe due to the extent of UPR inhibition, weight loss and hyperglycemia [ 158 ].…”

Exosomes as mediators of immune regulation and immunotherapy in cancer

“…Endoplasmic reticulum (ER) stress can impede the development of antitumor immune responses through reprogramming of several immune cell populations [116,117]. In macrophages, exosomes derived from liver cancer cells undergoing ER stress promoted the secretion of IL-6, MCP-1, IL-10, and TNF-a through STAT3 signaling [118].…”

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

“…Myeloid-derived suppressor cells (MDSCs) are characterized by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which induces the unfolded protein response (UPR) 140 , 141 . The UPR features an orchestrated upregulation of activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1α) and PKR-like endoplasmic reticulum kinase (PERK).…”