Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

Pantel, Austin R.; Teixeira, Angela; Haddad, Elias K.; Wood, Elizabeth G.; Steinman, Ralph M.; Longhi, M. Paula

doi:10.1371/journal.pbio.1001759

Cited by 179 publications

(195 citation statements)

References 44 publications

(54 reference statements)

Supporting

Mentioning

180

Contrasting

Unclassified

Order By: Relevance

“…The adaptation of DCs to changing metabolic states resulted from a mechanism of "metabolic checkpoint," an active signaling process involved in sensing metabolic alteration and subsequently signaling transaction and execution (56). Recent studies indicated that a Tolllike receptor signaling-mediated metabolic reprogramming is required for DC maturation and antigen presentation (57)(58)(59). Moreover, the dysregulated mTORC1 or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity results in an impaired DC development and maturation, indicating a metabolic checkpoint sensing amino acids and intracellular ATP during DC development and maturation (58,60).…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 ⁺ T cells through IL-12 and TGF-β1

Liu

Xue

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

103

View full text Add to dashboard Cite

The differentiation of naive CD4+ T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (TH1) cells and antiinflammatory Foxp3+ regulatory T cells (Treg cells). Genetic deletion of SIRT1 in DCs restrained the generation of Treg cells while driving TH1 development, resulting in an enhanced T-cell–mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1–HIF1α metabolic checkpoint in controlling T-cell lineage specification.

show abstract

Section: Discussionmentioning

confidence: 99%

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 ⁺ T cells through IL-12 and TGF-β1

Liu

Xue

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

103

View full text Add to dashboard Cite

show abstract

“…The glycolytic metabolism is known to regulate cytokine expression in activated immune cells (29)(30)(31)(32), as IL-6 expression in murine monocytic cell lines is lowered upon downregulation of the glycolytic pathway by 2-deoxyglucose (33), TNF-a is downregulated by lactate (34), and IL-1b expression is enhanced by a TLR-dependent stabilization of HIF-1a (35), a process further enhanced by succinate accumulation (36). Our data show that IL6, IL1B, and TNF mRNA are positively regulated by the glycolytic pathway in proinflammatory GM-MØ; whereas a drop of GM-MØ ECAR levels correlates with reduced IL6, IL1B, and TNF mRNA levels, inhibition of mitochondrial respiration leaves the expression of these cytokine genes unaffected.…”

Section: Discussionmentioning

confidence: 99%

Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

Izquierdo

Cuevas

Fernández-Arroyo

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Macrophages integrate information from the tissue microenvironment and adjust their effector functions according to the prevalent extracellular stimuli. Therefore, macrophages can acquire a variety of activation (polarization) states, and this functional plasticity allows the adequate initiation, regulation, and resolution of inflammatory responses. Modulation of the glucose metabolism contributes to the macrophage adaptation to the surrounding cytokine milieu, as exemplified by the distinct glucose catabolism of macrophages exposed to LPS/IFN-γ or IL-4. To dissect the acquisition of macrophage effector functions in the absence of activating cytokines, we assessed the bioenergetic profile of macrophages generated in the presence of GM-CSF (GM-MØ) or M-CSF (M-MØ), which do not release pro- or anti-inflammatory cytokines unless subjected to additional activating stimuli. Compared to M-MØ, GM-MØ displayed higher oxygen consumption rate and aerobic glycolysis (extracellular acidification rate [ECAR]), as well as higher expression of genes encoding glycolytic enzymes. However, M-MØ exhibited a significantly higher oxygen consumption rate/ECAR ratio. Surprisingly, whereas aerobic glycolysis positively regulated IL1B, TNF, and INHBA mRNA expression in both macrophage subtypes, mitochondrial respiration negatively affected IL6, IL1B, TNF, and CXCL10 mRNA expression in M-MØ. The physiological significance of these results became evident under low oxygen tensions, as hypoxia enhanced ECAR in M-MØ via HIF-1α and HIF-2α, increased expression of glycolytic enzymes and GM-MØ–specific genes, and diminished expression of M-MØ–associated genes. Therefore, our data indicate that GM-MØ and M-MØ display distinct bioenergetic profiles, and that hypoxia triggers a transcriptomic switch in macrophages by promoting a HIF-1α/HIF-2α-dependent increase in ECAR.

show abstract

Section: Switching To Warburg Metabolism Allows Cellular Activation Amentioning

confidence: 99%

“…Despite the fact that mouse classical DCs do not express Nos2, they do exhibit diminished mitochondrial activity and enhanced glycolysis over the long term after activation with TLR agonists in vivo. These changes are reported to be driven by autocrine type I interferon signaling through HIF-1α (Pantel et al, 2014).Core nutrient/energy-sensing pathways in metabolic reprogramming in DCs Cells possess central signaling pathways that are able to sense nutrient and/or energy status and adjust metabolism to be anabolic or catabolic as required. Cellular growth requires anabolic metabolism, and this can be regulated by mTORC1 downstream of PI3K/Akt and growth factor receptors (Fig.…”

mentioning

confidence: 99%

Immunometabolism governs dendritic cell and macrophage function

O’Neill¹,

Pearce²

2016

J Cell Biol

View full text Add to dashboard Cite

The main challenge of metabolic pathways has always been their complexity. This stems from the number of metabolites (which intracellularly can run into the thousands), their chemical complexity, and the sophisticated regulation of the enzymes that control them. Recent discoveries on the role of metabolic pathways in immune cell function have brought the burgeoning area of immunometabolism to the forefront for many immunologists. In this review, we will discuss recent findings in macrophages and DCs, critical cell types for both innate and adaptive immunity. A primary goal for immunologists is to uncover the molecular players in processes that provide a detailed account of how the effector functions of immune cells are controlled. These processes become dysregulated in disease. The analysis of metabolic reprogramming in macrophages and DCs provides new insights into how these cells perform their functions, including cytokine production, phagocytosis, or antigen presentation. The somewhat surprising finding is that metabolic processes such as glycolysis, the Krebs cycle, and fatty acid metabolism have highly specific effects on macrophage and DC function. The manipulation of these pathways can dramatically alter the functioning of these cells in specific ways, rather than simply being involved in energy generation or general biosynthesis. Metabolic reprogramming as a phenomenon is therefore joining other key immunoregulatory events that govern the nature of the immune response, both in health and disease. What is metabolic reprogramming?A simple view of metabolic reprogramming is that it reflects the responses of cells to critical changes in the environment. For example, under normoxic conditions, cells can use oxidative phosphorylation (OXP HOS) to generate ATP. Critical components of the electron transport chain (ETC) use NADH and FADH generated as a result of reactions in the Krebs cycle, which in turn is fueled by glucose, fatty acids, and glutamine. In contrast, when O 2 tensions are low, cells can to a greater or lesser degree generate ATP through glycolysis and independently of OXP HOS, but this pathway is highly dependent on glucose as a sole fuel source. The core metabolic pathways are essential for interchanging carbons between sugars, fatty acids, nucleic acids, and proteins, and therefore, metabolic flexibility can play a critical role as prevailing nutrient and oxygen conditions change. This can be of great importance if a cell is faced with differing functional demands. A critical point from the perspective of this review is that recent work has emphasized the fact that changes in key metabolic regulatory events in immune cells can be initiated not only by nutrient and oxygen conditions, but also in reprogramming events downstream of ligation of pattern recognition receptors (PRRs), cytokine receptors, and/or Ag receptors (and likely other receptors). Thus, in immune cells, there is the potential for metabolic changes to occur in response to instructional signals received from other cells or from ch...

show abstract

Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

Abstract: Type I IFN signaling is indispensable for the maturation of dendritic cells (DCs) that are required to elicit an immune response, and it also controls a shift in cellular metabolism to meet the increased energy demands of DC maturation.

Cited by 179 publications

References 44 publications

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 ⁺ T cells through IL-12 and TGF-β1

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 ⁺ T cells through IL-12 and TGF-β1

Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

Immunometabolism governs dendritic cell and macrophage function

Contact Info

Product

Resources

About

Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

Abstract: Type I IFN signaling is indispensable for the maturation of dendritic cells (DCs) that are required to elicit an immune response, and it also controls a shift in cellular metabolism to meet the increased energy demands of DC maturation.

Cited by 179 publications

References 44 publications

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 + T cells through IL-12 and TGF-β1

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 + T cells through IL-12 and TGF-β1

Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

Immunometabolism governs dendritic cell and macrophage function

Contact Info

Product

Resources

About

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 ⁺ T cells through IL-12 and TGF-β1

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 ⁺ T cells through IL-12 and TGF-β1