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

Area of Science:

• Immunology
• Cell Biology
• Metabolic Pathways

Background:

• Dendritic cells (DCs) are crucial immune cells that bridge innate and adaptive immunity.
• DC activation by pathogen-associated molecular patterns (PAMPs) involves significant bioenergetic reprogramming.
• Understanding these metabolic shifts is key to modulating immune responses.

Purpose of the Study:

• To investigate the impact of metabolic alterations on DC function and cytokine production.
• To explore the role of the endoplasmic reticulum (ER) stress response in PAMP-stimulated DCs.
• To elucidate the specific signaling pathways involved in IL-23A induction.

Main Methods:

• Human monocyte-derived DCs were stimulated with PAMPs and treated with glucose modulators (glucose starvation, 2-deoxy-d-glucose [2-DG]).
• ER stress inducers (tunicamycin, thapsigargin) were used to assess their effect on cytokine expression.
• Signaling pathway activation (IRE1α, PERK) was analyzed, along with genetic studies in conditional knockout mice.

Main Results:

• PAMP stimulation enhanced glycolysis in DCs, while oxidative phosphorylation remained unchanged.
• 2-DG treatment, unlike glucose deprivation, markedly induced IL-23A expression.
• ER stress, particularly via IRE1α and PERK pathways, was shown to be a potent driver of IL-23A production in PAMP-stimulated DCs.

Conclusions:

• The endoplasmic reticulum (ER) stress response significantly modulates cytokine expression in PAMP-stimulated human DCs.
• IL-23A induction is dependent on specific ER stress signaling pathways (IRE1α/XBP1 or PERK/C/EBPβ) based on the type of PAMP stimulation.
• These findings reveal a novel link between cellular stress responses and immune cell function.