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Review
. 2018 Mar 5:9:422.
doi: 10.3389/fimmu.2018.00422. eCollection 2018.

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

Judith A Smith  1   2
Affiliations
Review

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

Judith A Smith. Front Immunol. .

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.

Keywords: autoimmunity; autoinflammatory disease; bacteria; cytokine regulation; endoplasmic reticulum stress; infection; unfolded protein response; virus.

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Figures

Figure 1
Figure 1
Amplification of pathogen immune responses via endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Pathogens cause tissue damage, intracellular host stress, and stimulate pattern recognition receptors (PRRs) which then induce cytokines. Multiple pathogen-triggered cellular insults cause stress in the ER that impacts protein folding and thus induces the UPR. The UPR, PRR activation, and cytokine production intersects on multiple levels (see main text and Figure 3), with interactions going in both directions (blue two-sided arrows). This amplification mechanism generates an immune response commensurate with the degree of pathogenic threat.
Figure 2
Figure 2
Three pathways of the unfolded protein response (UPR). (1) inositol requiring enzyme 1 (IRE1) pathway (left, green), a dual endonuclease and kinase, binds the chaperone binding protein (BiP) in its monomeric state. On sensing unfolded/misfolded protein IRE1 oligomerizes and auto-trans phosphorylates (red Ps). Activation of the endonuclease specifically splices 26 nucleotides out of the XBP1 mRNA, causing a frameshift mutation that removes a premature stop codon, thus enabling translation of the full length transcription factor. With increased stress, the non-specific endonuclease function cleaves endoplasmic reticulum (ER)-associated mRNAs in a process called regulated IRE1-dependent decay (RIDD). The IRE1 kinase domain associates with other signaling partners that phosphorylate Jun N-terminal kinase (JNK). ERAD, ER-associated degradation. (2) Activating transcription factor 6 (ATF6) pathway (middle, blue): ATF6 release of BiP uncovers a Golgi localization signal (GLS) enabling translocation to the Golgi. There it is cleaved by Site-1 and Site-2 proteases (scissors), liberating the ATF6 transcription factor. (3) Protein kinase R like endoplasmic reticulum kinase (PERK) pathway (right, pink): in the presence of phosphorylated protein, PERK also oligomerizes and transphosphorylates, activating its kinase activity. PERK in turn phosphorylates eIF2α, resulting in transient global translational inhibition apart from a few specific mRNAs such as ATF4. ATF4 promotes transcription of the apoptosis-inducing transcription factor C/EBP homologous protein (CHOP). Cellular processes altered by the UPR pathways and key gene targets that are UPR components are in boxes.
Figure 3
Figure 3
Intersections of endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and immune signaling. ER stress and the UPR impact innate immune signaling and cytokine production on many levels between pathogen-sensing pattern recognition receptors (PRRs) and ultimate cytokine production: (1) PRR activation: ER stress and the UPR activate multiple PRRs (purple) including stimulator of interferon gene (STING), NLRP3, and other inflammasomes via thioredoxin-interacting protein (TXNIP) upregulation and reactive oxygen species (ROS), and the NOD1/2 receptors. Much of this interaction occurs at the mitochondrial-ER interface, where released calcium (Ca2+) and ROS feed into PRR activation. (2) The UPR enhances inflammatory signaling pathways leading to mitogen-activated protein kinase activation [IRE1 shown here, but protein kinase R-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) also impact ERK and p38 activation], and inhibitory factor κB (IκB) phosphorylation and degradation. (3) Transcription factors: the UPR activates canonical pro-inflammatory and IFN-regulatory transcription factors activator protein 1 (AP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and IRF3. Core UPR generated transcription factors such as XBP1 and C/EBP homologous protein (CHOP) also directly stimulate cytokine production by binding cytokine promoter and enhancer elements.
Figure 4
Figure 4
Autoimmune and autoinflammatory diseases involving the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. Aberrant or excess cytokine production plays a key role in driving autoimmune and autoinflammatory disorders. Interestingly, ER stress and/or the UPR has been increasingly implicated in these same diseases. Thus, the multiple mechanisms by which the UPR interacts with cytokines (both cytokines inducing ER stress and UPR regulating cytokine production) have repercussions for the pathogenesis of inflammatory diseases. Several of the diseases highlighted in this review and the prominent features surrounding ER stress and cytokine induction are in boxes. More autoinflammatory disorders are to the left and autoimmune on the right.
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