Human Plasmacytoid and Monocyte-Derived Dendritic Cells Display Distinct Metabolic Profile Upon RIG-I Activation

Recent advances reveal that metabolic reprogramming is required for adequate antiviral responses of dendritic cells (DCs) that possess the capacity to initiate innate and adaptive immune responses. Several reports indicate that Toll-like receptor (TLR) stimulation of DCs is accompanied by a rapid induction of glycolysis; however, the metabolic requirements of retinoic-acid inducible gene I (RIG-I)-like receptor (RLR) activation have not defined either in conventional DCs (cDCs) or in plasmacytoid DCs (pDCs) that are the major producers of type I interferons (IFN) upon viral infections. To sense viruses and trigger an early type I IFN response, pDCs rely on endosomal TLRs, whereas cDCs employ cytosolic RIG-I, which is constitutively present in their cytoplasm. We previously found that RIG-I is upregulated in pDCs upon endosomal TLR activation and contributes to the late phase of type I IFN responses. Here we report that TLR9-driven activation of human pDCs leads to a metabolic transition to glycolysis supporting the production of type I IFNs, whereas RIG-I-mediated antiviral responses of pDCs do not require glycolysis and rather rely on oxidative phosphorylation (OXPHOS) activity. In particular, TLR9-activated pDCs show increased extracellular acidification rate (ECAR), lactate production, and upregulation of key glycolytic genes indicating an elevation in glycolytic flux. Furthermore, administration of 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, significantly impairs the TLR9-induced secretion of type I IFNs by human pDCs. In contrast, RIG-I stimulation of pDCs does not result in any alterations of ECAR, and type I IFN production is not inhibited but rather promoted by 2-DG treatment. Moreover, pDCs activated via TLR9 but not RIG-I in the presence of 2-DG are impaired in their capacity to prime allogeneic naïve CD8+ T cell proliferation. Interestingly, human monocyte-derived DCs (moDC) triggered via RIG-I show a commitment to glycolysis to promote type I IFN production and T cell priming in contrast to pDCs. Our findings reveal for the first time, that pDCs display a unique metabolic profile; TLR9-driven but not RIG-I-mediated activation of pDCs requires glycolytic reprogramming. Nevertheless, the metabolic signature of RIG-I-stimulated moDCs is characterized by glycolysis suggesting that RIG-I-induced metabolic alterations are rather cell type-specific and not receptor-specific

Current translational potential and underlying molecular mechanisms of necroptosis

Cell death has a fundamental impact on the evolution of degenerative disorders, autoimmune processes, inflammatory diseases, tumor formation and immune surveillance. Over the past couple of decades extensive studies have uncovered novel cell death pathways, which are independent of apoptosis. Among these is necroptosis, a tightly regulated, inflammatory form of cell death. Necroptosis contribute to the pathogenesis of many diseases and in this review, we will focus exclusively on necroptosis in humans. Necroptosis is considered a backup mechanism of apoptosis, but the in vivo appearance of necroptosis indicates that both caspase-mediated and caspase-independent mechanisms control necroptosis. Necroptosis is regulated on multiple levels, from the transcription, to the stability and posttranslational modifications of the necrosome components, to the availability of molecular interaction partners and the localization of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Accordingly, we classified the role of more than seventy molecules in necroptotic signaling based on consistent in vitro or in vivo evidence to understand the molecular background of necroptosis and to find opportunities where regulating the intensity and the modality of cell death could be exploited in clinical interventions. Necroptosis specific inhibitors are under development, but >20 drugs, already used in the treatment of various diseases, have the potential to regulate necroptosis. By listing necroptosis-modulated human diseases and cataloging the currently available drug-repertoire to modify necroptosis intensity, we hope to kick-start approaches with immediate translational potential. We also indicate where necroptosis regulating capacity should be considered in the current applications of these drugs

Differences in the sensitivity of classically and alternatively activated macrophages to TAK1 inhibitor-induced necroptosis

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Doxorubicin induces large-scale and differential H2A and H2B redistribution in live cells

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RNA-DNA hybrid (R-loop) immunoprecipitation mapping: an analytical workflow to evaluate inherent biases

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Damage-mediated macrophage polarization in sterile inflammation

Most of the leading causes of death, such as cardiovascular diseases, cancer, dementia, neurodegenerative diseases, and many more, are associated with sterile inflammation, either as a cause or a consequence of these conditions. The ability to control the progression of inflammation toward tissue resolution before it becomes chronic holds significant clinical potential. During sterile inflammation, the initiation of inflammation occurs through damage-associated molecular patterns (DAMPs) in the absence of pathogen-associated molecules. Macrophages, which are primarily localized in the tissue, play a pivotal role in sensing DAMPs. Furthermore, macrophages can also detect and respond to resolution-associated molecular patterns (RAMPs) and specific pro-resolving mediators (SPMs) during sterile inflammation. Macrophages, being highly adaptable cells, are particularly influenced by changes in the microenvironment. In response to the tissue environment, monocytes, pro-inflammatory macrophages, and pro-resolution macrophages can modulate their differentiation state. Ultimately, DAMP and RAMP-primed macrophages, depending on the predominant subpopulation, regulate the balance between inflammatory and resolving processes. While sterile injury and pathogen-induced reactions may have distinct effects on macrophages, most studies have focused on macrophage responses induced by pathogens. In this review, which emphasizes available human data, we illustrate how macrophages sense these mediators by examining the expression of receptors for DAMPs, RAMPs, and SPMs. We also delve into the signaling pathways induced by DAMPs, RAMPs, and SPMs, which primarily contribute to the regulation of macrophage differentiation from a pro-inflammatory to a pro-resolution phenotype. Understanding the regulatory mechanisms behind the transition between macrophage subtypes can offer insights into manipulating the transition from inflammation to resolution in sterile inflammatory diseases

Cytotoxic activity of human dendritic cells induces RIPK1-dependent cell death

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