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The unfolded protein response in immunity and inflammation

Key Points

  • The unfolded protein response (UPR) has an important role in the differentiation and maturation of various immune cells and is crucial for immune cell function, such as cytokine production by macrophages and cross-presentation by dendritic cells, for example.

  • Innate immune signalling differentially affects the three arms of the UPR to optimize inflammatory responses, while simultaneously inhibiting the activation of the terminal UPR, which is associated with cell death. This allows the cell to survive and manage temporary increases in protein production during immune responses to pathogens.

  • In complex autoimmune diseases, chronic activation of the UPR can function as the nidus for the development of inflammation.

  • UPR activation triggers inflammatory responses mainly through nuclear factor-κB (NF-κB) activation, phosphorylation of JUN N-terminal kinase (JNK), activation of the inflammasome and direct interaction of downstream UPR targets with the promoters of inflammatory cytokine genes.

  • UPR activation in cancer cells may interfere with antitumour immunity, which indicates that manipulating UPR signalling could boost antitumour immune responses.

  • The UPR is amenable to therapeutic manipulation to either promote its beneficial homeostasis-inducing properties and/or inhibit its inflammation-inducing activities in the setting of unresolved endoplasmic reticulum (ER) stress.

Abstract

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.

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Figure 1: The accumulation of unfolded proteins in the ER lumen activates the three arms of the UPR.
Figure 2: XBP1 has a crucial role in plasma cell differentiation and DC differentiation and function.
Figure 3: TLR signalling and the UPR coordinate immune responses in macrophages.
Figure 4: UPR signalling in intestinal epithelial cells.
Figure 5: The UPR as an inflammatory nidus.

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Acknowledgements

The authors thank M. Wang for assistance with preparation of this Review and apologize to those whose work was not included owing to size limitations. This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); NIH grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).

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Glossary

ER-associated degradation

(ERAD). A pathway that removes terminally misfolded proteins from the endoplasmic reticulum (ER) through their retrotranslocation to the cytosol, which targets them for degradation by the ubiquitin–proteasome system.

Unfolded protein response

(UPR). A highly conserved pathway that regulates the balance between the folding capacity of the endoplasmic reticulum (ER) and protein synthesis.

Integrated stress response

(ISR). An ancient stress response that modulates protein biosynthesis by integrating various types of stress signals, including endoplasmic reticulum (ER) stress, amino acid deprivation, virus infection and oxidative stress.

Paneth cells

Highly specialized small-intestinal epithelial cells that shape the composition of the microbiota through the secretion of antimicrobial proteins and that sustain and modulate epithelial stem cells by the secretion of niche factors.

Acute phase response

(APR). A group of systemic and innate physiological processes in the early response to infection or injury.

Crohn's disease

An inflammatory disease of the small and large intestines that is thought to arise from an inappropriate immune response towards the intestinal microbiota in a genetically susceptible host.

Ulcerative colitis

A chronic disease of the colon with unknown aetiology, characterized by inflammation and ulceration in the colon.

Non-alcoholic fatty liver disease

(NAFLD). Liver disease characterized by the accumulation of fat (steatosis) in the liver, which is often associated with obesity. Although NAFLD is benign, it can progress towards steatohepatitis and even cirrhosis.

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Grootjans, J., Kaser, A., Kaufman, R. et al. The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16, 469–484 (2016). https://doi.org/10.1038/nri.2016.62

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