The unfolded protein response in immunity and inflammation

Abstract

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.