Endoplasmic reticulum and oxidative stress in immunopathology: understanding the crosstalk between cellular stress and inflammation

An imbalance in protein production is common to several diseases. Endoplasmic reticulum (ER) stress occurs when proteins misfold during biosynthesis, resulting in reduced production of cell surface and secreted proteins. Misfolding activates cellular stress pathways including the unfolded protein response (UPR), the production of reactive oxygen and nitrogen species and a state of oxidative stress. Oxidative stress and ER stress are integrally entwined states, implicated in the aetiology of many diseases, diabetes and obesity, arthritis and spondyloarthropathies, multiple forms of respiratory inflammation, inflammatory bowel diseases, infections and cancer. Consequently, there is substantial interest in therapeutic targeting of stress in a variety of disorders. Major intracellular stress response pathways triggered by oxidative stress and ER stress (UPR) in turn regulate inflammatory pathways. Oxidative stress results from an imbalance between oxidants [reactive oxygen species (ROS) and reactive nitrogen species (RNS)] derived from the local environment or produced within cells and cellular antioxidants. Protein folding in the ER results in production of ROS, which are deactivated by endogenous antioxidants such as glutathione peroxidase and superoxide dismutase. Despite ERresident chaperones and enzymes that promote correct protein folding, a proportion of all proteins misfold. Factors known to increase misfolding include ROS and RNS, increased protein synthesis, microbial toxins, viral infection and cytokines. Prolonged or severe ER stress can induce inflammation, autophagy and apoptosis (Figure 1). The mechanisms by which ER stress influences pathology, and is interlinked with inflammation and oxidative stress, are covered by the reviews in this Special Feature of Clinical & Translational Immunology. Our understanding of the crosstalk between different cellular stress pathways and inflammation is constantly evolving. Pickering et al. describe the increase in hyperglycaemiainduced ROS is associated with increased lowgrade chronic inflammation resulting in diabetic complications such as cardiovascular disease, chronic kidney disease and retinopathy. They raise an interesting possibility of utilising antiinflammatory drugs that have dual effects – on inflammation and on oxidative stress – and that potentially a combination of the two might be an approach to improve disease outcomes in diabetic complications more effectively. Excessive production of monoclonal immunoglobulin is a key feature of multiple myeloma. Nikesitch et al. describe that this increased protein production induces ER stress and activates the proteosomal degradation pathways to avoid accumulation of the protein in the ER and the consequent cell death. Proteosomal inhibitors have been quite effective, but unfortunately, there is increased resistance to therapies such as bortezomib. There is a need for development of treatments that could include autophagy inhibitors, heat-shock protein inhibitors or ubiquitin ligase inhibitors. However, resistance to such drugs might be a possibility; therefore, drugs that could specifically target resistance to proteasome inhibitors or resensitise multiple myeloma to proteasome inhibitors