Endoplasmic Reticulum Stress Sensor IRE1α Enhances IL-23 Expression by Human Dendritic Cells

Abstract

Human monocyte-derived dendritic cells (DCs) exposed to pathogen-associated molecular patterns (PAMPs) undergo bioenergetic changes that influence the immune response. We found that stimulation with PAMPs enhanced glycolysis in DCs, whereas oxidative phosphorylation remained unaltered. Glucose starvation and the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) modulated cytokine expression in stimulated DCs. Strikingly, IL23A was markedly induced upon 2-DG treatment, but not during glucose deprivation. Since 2-DG can also rapidly inhibit protein N-glycosylation, we postulated that this compound could induce IL-23 in DCs via activation of the endoplasmic reticulum (ER) stress response. Indeed, stimulation of DCs with PAMPs in the presence of 2-DG robustly activated inositol-requiring protein 1α (IRE1α) signaling and to a lesser extent the PERK arm of the unfolded protein response. Additional ER stressors such as tunicamycin and thapsigargin also promoted IL-23 expression by PAMP-stimulated DCs. Pharmacological, biochemical, and genetic analyses using conditional knockout mice revealed that IL-23 induction in ER stressed DCs stimulated with PAMPs was IRE1α/X-box binding protein 1-dependent upon zymosan stimulation. Interestingly, we further evidenced PERK-mediated and CAAT/enhancer-binding protein β-dependent trans-activation of IL23A upon lipopolysaccharide treatment. Our findings uncover that the ER stress response can potently modulate cytokine expression in PAMP-stimulated human DCs.

Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

“…Different branches of the UPR are involved in the homeostasis and the control of immune responses in DC (Janssens et al, 2014;Osorio et al, 2014;Tavernier et al, 2017). XBP1 regulates transcription of IL-6 and TNF in mouse macrophages (Martinon et al, 2010) and IL-23 production in human DC in response to zymosan (Márquez et al, 2017), while CHOP increases IL-23 expression in human DC in response to LPS and tunicamycin (Goodall et al, 2010). However, whether these effects require metabolic adaptations has not been investigated.…”

Shaping of Dendritic Cell Function by the Metabolic Micro-Environment

“…Moreover, treatment of LPS-activated moDCs with 2-DG has been documented to result in ER-induced upregulation of IL-23 expression, while glucose depletion did not. These data indicate that the effects of 2-DG are not always connected to glycolysis and warrant caution when interpreting data from studies that have used 2-DG to interrogate the role of glycolysis in DC biology ( 29 ). In addition, most of the studies described above have been performed in BMDCs, in which iNOS plays a major role in the suppression of mitochondrial respiration in response to TLR stimulation.…”

IRE1α Implications in Endoplasmic Reticulum Stress-Mediated Development and Pathogenesis of Autoimmune Diseases

“…The IL-17 and IL-23 cytokines including IL-23R are highly activated during HLA-B27 misfolding and UPR activation ( 198 , 201 ). The production of these cytokines during HLA-B27-induced UPR is mainly contributed from the IRE1α/XBP1s pathway, which enhances IL-23 production during ER stress ( 202 , 203 ). In addition, IFN-α, IFN-β, or TNFα stimulation in HLA-B27 overexpressing transgenic rats enhanced the BiP and spliced XBP1 compared to wild-type rats ( 201 , 204 ).…”

“…These studies demonstrate that the inflammatory effects of XBP1s are differentially regulated and may depend on the stress intensity. IRE1α also enhances IL-23 expression in DCs ( 203 ). This causes the massive T-cell infiltration within the islets and ultimately results in β cell destruction.…”