Key Points
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The endoplasmic reticulum (ER) constantly monitors the amount and conformational status of secreted and membrane-related proteins
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The ER rapidly activates multiple signalling pathways in response to changes in the quality and quantity of the proteins it processes, levels of reactive oxygen species and metabolic changes
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The ER is an intracellular nexus of the innate and adaptive immune response pathways
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Disrupted ER homeostasis has an important role in the pathogenesis of many diseases, including several rheumatic diseases
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ER stress signalling pathways are important in several immune and somatic cell types implicated in disease pathways: fibroblast-like synoviocytes, myeloid cells, myocytes, endothelial cells, B cells, chondrocytes and epithelial cells
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Future therapies that target ER signalling pathways have potential applications in many rheumatic diseases
Abstract
Rheumatic diseases represent a heterogeneous group of inflammatory conditions, many of which involve chronic activation of both innate and adaptive immune responses by multiple genetic and environmental factors. These immune responses involve the secretion of excessive amounts of cytokines and other signalling mediators by activated immune cells. The endoplasmic reticulum (ER) is the cellular organelle that directs the folding, processing and trafficking of membrane-bound and secreted proteins, including many key components of the immune response. Maintaining homeostasis in the ER is critical to cell function and survival. Consequently, elaborate mechanisms have evolved to sense and respond to ER stress through three main signalling pathways that together comprise the unfolded protein response (UPR). Activation of the UPR can rapidly resolve the accumulation of misfolded proteins, direct permanent changes in the size and function of cells during differentiation, and critically influence the immune response and inflammation. Recognition of the importance of ER stress and UPR signalling pathways in normal and dysregulated immune responses has greatly increased in the past few years. This Review discusses several settings in which ER stress contributes to the pathogenesis of rheumatic diseases and considers some of the therapeutic opportunities that these discoveries provide.
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Acknowledgements
The research of R.A.C. and F.N. is supported by the NIH and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Intramural Research Program grant ZO1-AR-041184.
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Both authors researched the data for this article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.
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R.A.C. declares that he has been the Principal Investigator on a cooperative research and development agreement between Eli Lilly and the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). F.N. declares no competing interests.
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Navid, F., Colbert, R. Causes and consequences of endoplasmic reticulum stress in rheumatic disease. Nat Rev Rheumatol 13, 25–40 (2017). https://doi.org/10.1038/nrrheum.2016.192
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DOI: https://doi.org/10.1038/nrrheum.2016.192
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