Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity

Abstract

Protein folding in the endoplasmic reticulum (ER) is an essential cell function. To safeguard this process in the face of environmental threats and internal stressors, cells mount an evolutionarily conserved response known as the unfolded protein response (UPR). Invading pathogens induce cellular stress that impacts protein folding, thus the UPR is well situated to sense danger and contribute to immune responses. Cytokines (inflammatory cytokines and interferons) critically mediate host defense against pathogens, but when aberrantly produced, may also drive pathologic inflammation. The UPR influences cytokine production on multiple levels, from stimulation of pattern recognition receptors, to modulation of inflammatory signaling pathways, and the regulation of cytokine transcription factors. This review will focus on the mechanisms underlying cytokine regulation by the UPR, and the repercussions of this relationship for infection and autoimmune/autoinflammatory diseases. Interrogation of viral and bacterial infections has revealed increasing numbers of examples where pathogens induce or modulate the UPR and implicated UPR-modulated cytokines in host response. The flip side of this coin, the UPR/ER stress responses have been increasingly recognized in a variety of autoimmune and inflammatory diseases. Examples include monogenic disorders of ER function, diseases linked to misfolding protein (HLA-B27 and spondyloarthritis), diseases directly implicating UPR and autophagy genes (inflammatory bowel disease), and autoimmune diseases targeting highly secretory cells (e.g., diabetes). Given the burgeoning interest in pharmacologically targeting the UPR, greater discernment is needed regarding how the UPR regulates cytokine production during specific infections and autoimmune processes, and the relative place of this interaction in pathogenesis.

Altered platelet proteome in lupus anticoagulant (LA)-positive patients—protein disulfide isomerase and NETosis as new players in LA-related thrombosis

“…Several proteins showing a positive correlation with aPLAs act as chaperones in the endoplasmic reticulum, including PDI family members, GRP78 and CALR. These findings indicate the induction of the unfolded protein response, a cellular stress response related to endoplasmic reticulum stress 57 , and therefore higher cellular stress in LA-positive patients, which is in accordance with another study 48 . Interestingly, autoimmune diseases are associated with the unfolded protein response, which has been discussed as a potential pharmacological target to counteract autoantigen generation and presentation 57 .…”

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

“…On one side, the nuclease domain cleaves two specific sites in the mRNA encoding XBP1, a conserved UPR transcription factor, which leads to XBP1 induction and translation through removal of a regulatory intron (Figure 1F). Afterward, XBP1s translocates into the nucleus and promotes the transcription of its target genes (90,91), including Il-6 whose downregulation was detected in BV-2 cells deprived of IRE1α endonuclease activity (Figure 3E). On the other hand, the RIDD pathway relieves the burden on the ER by degrading of mRNAs encoding mostly ER-targeted proteins.…”

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

“…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]. There are several reports indicating that ER stress could induce the expression and secretion of C-C motif chemokine ligand 2 (CCL2/MCP-1) in different cell types [76].…”