Plasmacytoid dendritic cells (pDCs) are innate immune sentinels uniquely specialised in the rapid and potent production of type I interferons (IFN-I) during viral infection. While this capacity is essential for antiviral defence, sustained pDC activation is a central feature of numerous autoimmune and inflammatory disorders. Although the molecular pathways governing nucleic acid sensing and IFN-I induction have been extensively characterised, the metabolic and redox mechanisms that support, and limit pDC function remain incompletely understood. Emerging studies reveal that pDC activity is tightly linked to a specialised redox-metabolic programme involving mitochondrial respiration, reactive oxygen species (ROS), and endolysosomal signalling networks. In this review, we integrate current evidence to propose that pDCs operate within a tightly regulated redox window that permits effective acute antiviral responses but renders them vulnerable to metabolic stress and dysregulation upon chronic stimulation. We examine how mitochondrial fitness, NAD + homeostasis, ROS dynamics, and endolysosomal redox control collectively influence pDC activation, resolution of inflammation, and pathogenic persistence. By reframing pDC biology through a redox-metabolic perspective, we highlight new conceptual insights into IFN-I-driven disease and identify potential therapeutic strategies to selectively modulate pathogenic pDC responses. • A defined redox window enables antiviral IFN-I responses in pDCs • ROS act as signalling mediators rather than mere by-products • Metabolic checkpoints integrate mitochondrial and lysosomal pathways • Chronic stimulation disrupts redox balance and sustains inflammation • Targeting redox metabolism may selectively modulate pathogenic pDCs
Rueschpler et al. (Wed,) studied this question.