ER Stress Activates the NLRP3 Inflammasome: A Novel Mechanism of Atherosclerosis

Abstract

The endoplasmic reticulum (ER) is an important organelle that regulates several fundamental cellular processes, and ER dysfunction has implications for many intracellular events. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is an intracellularly produced macromolecular complex that can trigger pyroptosis and inflammation, and its activation is induced by a variety of signals. ER stress has been found to affect NLRP3 inflammasome activation through multiple effects including the unfolded protein response (UPR), calcium or lipid metabolism, and reactive oxygen species (ROS) generation. Intriguingly, the role of ER stress in inflammasome activation has not attracted a great deal of attention. In addition, increasing evidence highlights that both ER stress and NLRP3 inflammasome activation contribute to atherosclerosis (AS). AS is a common cardiovascular disease with complex pathogenesis, and the precise mechanisms behind its pathogenesis remain to be determined. Both ER stress and the NLRP3 inflammasome have emerged as critical individual contributors of AS, and owing to the multiple associations between these two events, we speculate that they contribute to the mechanisms of pathogenesis in AS. In this review, we aim to summarize the molecular mechanisms of ER stress, NLRP3 inflammasome activation, and the cross talk between these two pathways in AS in the hopes of providing new pharmacological targets for AS treatment.

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…In acute injuries, inflammation restores tissue homeostasis but prolonged inflammatory conditions stimulate the immunosuppressive network in an attempt to prevent excessive inflammatory damage in tissues (see below). There is clear evidence that ER stress can elicit inflammatory responses in many age-related diseases, e.g., atherosclerosis [72], hepatic steatosis [73], and age-related macular degeneration [74]. It seems that the activation of inflammasomes is involved in the crosstalk between ER stress and inflammatory responses in some diseases [72,73].…”

“…There is clear evidence that ER stress can elicit inflammatory responses in many age-related diseases, e.g., atherosclerosis [72], hepatic steatosis [73], and age-related macular degeneration [74]. It seems that the activation of inflammasomes is involved in the crosstalk between ER stress and inflammatory responses in some diseases [72,73]. Given its role as an alarming mechanism, ER stress stimulates the secretion of chemokines and cytokines which subsequently recruit immune cells into tissues and activate their inflammatory function [75].…”

A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma

“…Myeloma cells treated with D089 also produced higher levels of reactive oxygen species (ROS) and experienced disruption of their mitochondrial membrane potential, additional hallmarks of ER stress. The convergence of ER signals can result in both the activation of inflammasomes [ 27 , 35 , 60 , 61 , 62 , 63 ] and the upregulation of DDIT3 which encodes C/EBP homologous protein (CHOP), a transcription factor which commits the cell to PCD [ 64 , 65 ].…”

Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis

“…Later studies revealed that the ER expansion occurs concomitantly with cytoskeleton modifications and subsequent cell size increase [ 219 , 224 ], once again reflecting the interplay between different cellular components. Importantly, convincing findings have also shown that ER stress can prompt inflammatory responses in several age-associated diseases, including atherosclerosis [ 225 ]. In particular, the incidence of chronic endothelial ER stress and activation of the UPR have been demonstrated in vivo at arterial sites susceptible to atherosclerosis [ 226 ].…”