Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression

Abstract

The endoplasmic reticulum (ER) stress response detects malfunctions in cellular physiology, and microbial pattern recognition receptors recognize external threats posed by infectious agents. This study has investigated whether proinflammatory cytokine expression by monocyte-derived dendritic cells is affected by the induction of ER stress. Activation of ER stress, in combination with Toll-like receptor (TLR) agonists, markedly enhanced expression of mRNA of the unique p19 subunit of IL-23, and also significantly augmented secretion of IL-23 protein. These effects were not seen for IL-12 secretion. The IL-23 gene was found to be a target of the ER stressinduced transcription factor C/EBP homologous protein (CHOP), which exhibited enhanced binding in the context of both ER stress and TLR stimulation. Knockdown of CHOP in U937 cells significantly reduced the synergistic effects of TLR and ER stress on IL-23p19 expression, but did not affect expression of other LPS-responsive genes. The integration of ER stress signals and the requirement for CHOP in the induction of IL-23 responses was also investigated in a physiological setting: infection of myeloid cells with Chlamydia trachomatis resulted in the expression of CHOP mRNA and induced the binding of CHOP to the IL-23 promoter. Furthermore, knockdown of CHOP significantly reduced the expression of IL-23 in response to this intracellular bacterium. Therefore, the effects of pathogens and other environmental factors on ER stress can profoundly affect the nature of innate and adaptive immune responses.T he mammalian innate immune system detects external threats by identifying components of microorganisms, using pattern recognition receptors (PRR) expressed on macrophages and dendritic cells (DC). Following PRR engagement, DCs link the innate and adaptive immune responses by producing cytokines that modulate T-cell responses.Threats to the internal homeostasis of the cell can be detected within the endoplasmic reticulum (ER) and the unfolded protein response (UPR) is triggered when there is an imbalance between protein synthesis and the folding capacity of the ER (e.g., when protein secretion is rapidly up-regulated) (1). Three sentinel ER proteins, ATF6, PERK, and IRE-1, initiate independent signaling pathways that elicit the UPR; these pathways have both unique and shared gene targets.PERK activation leads to decreased efficiency of protein translation via phosphorylation of eIF2α, but this translation "shut down" also potentiates ATF4 gene expression, resulting in activation of downstream ER stress-response pathways, including expression of C/EBP homologous protein (CHOP) and growth-arrest and DNA damage inducible protein GADD34. If homeostatic processes fail to resolve ER stress, CHOP activates apoptosis (2), whereas GADD34 dephosphorylates eIF2α to allow resumption of protein synthesis and survival (3). Activated IRE-1 acquires RNase activity and splices XBP-1 mRNA, which is then translated into a transcription factor that activates several UPR response genes (4). ...

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

“…Although evidence for a role of the UPR in the pathogenesis of AS is conflicting (15,16), it is clear that elements of the UPR are essential for the induction of IL-23 (17). We considered the possibility that the UPR might be specifically increased in male patients as a mechanism of the male sex bias in the Th17 axis (see Supplementary Figure 2, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/ art.39464/abstract).…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…4). Activation of IRE1 or XBP1, PERK, and CHOP in macrophages promotes the production of protumorigenic cytokines IL-6 and TNFa (114,115), and in DCs, CHOP promotes the production of proinflammatory IL-23, thereby favoring tumor growth (116). Similarly, deletion of ER-resident chaperone GRP96 in macrophages significantly reduced the abundance of IL-17A, IL-17F, IL-23, and TNFa in tumor-bearing mice (117).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Consistently, SFA-damaged hepatocytes secrete IL-8, which causes liver inflammation, contributing to the pathogenesis of nonalcoholic steatohepatitis (NASH) (Willy et al 2015). CHOP binds to and induces expression of IL-23p19, a key mediator of inflammation in dendritic cells (Goodall et al 2010). Infection of myeloid cells with bacteria induces CHOP transcription with subsequent induction of IL-23, which is greatly attenuated by knockdown of CHOP.…”