The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity

Domínguez‐Andrés, Jorge; Novakovic, Boris; Li, Yang; Scicluna, Brendon P.; Gresnigt, Mark S.; Arts, Rob J. W.; Oosting, Marije; Moorlag, Simone J.C.F.M.; Groh, Laszlo; Zwaag, Jelle; Koch, Rebecca M.; Horst, Rob ter; Joosten, Leo A. B.; Wijmenga, Cisca; Michelucci, Alessandro; Poll, Tom van der; Kox, Matthijs; Pickkers, Peter; Kumar, Vinod; Stunnenberg, Henk

doi:10.1016/j.cmet.2018.09.003

Cited by 252 publications

(236 citation statements)

References 49 publications

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“…Of note, itaconate-induced tolerance in human monocytes is counteracted by β-glucan-induced trained immunity as β-glucan inhibits the expression of immune-responsive gene 1 (IRG1) protein, the enzyme responsible for itaconate generation. Consistent with fumarate accumulation in β-glucan-trained monocytes 131 , β-glucan-mediated inhibition of IRG1 results in elevated expression of succinate dehydrogenase 138 . Thus, β-glucan-induced trained immunity is associated with enhanced succinate dehydrogenase activity and accumulation of fumarate as well as with reversing the endotoxin tolerance-inducing effects of itaconate, which acts as an antagonist of succinate dehydrogenase.…”

Section: Active Transcriptionmentioning

confidence: 71%

Defining trained immunity and its role in health and disease

et al. 2020

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| Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity. ✉

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Section: Active Transcriptionmentioning

confidence: 71%

Defining trained immunity and its role in health and disease

et al. 2020

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“…In summary, we found that PDC stimulation through pharmacologic inhibition of PDK by DCA increased TCA cycle intermediates that supply anabolic metabolites and decreased itaconate levels, a critical TCA cycle pivot for regulating the balance of immune resistance and tolerance. 54 PDC stimulation by DCA also rebalanced low levels of many amino acids and increased BCAA anaplerosis. Taken together, the monocyte cell model introduces the concept that PDC and itaconate crosstalk might couple to metabolic and immune fitness during inflammatory shock.…”

Section: Discussionmentioning

confidence: 92%

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Zhu

Long

Zabalawi

et al. 2020

Journal of Leukocyte Biology

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The pyruvate dehydrogenase complex (PDC)/pyruvate dehydrogenase kinase (PDK) axis directs the universal survival principles of immune resistance and tolerance in monocytes by controlling anabolic and catabolic energetics. Immune resistance shifts to immune tolerance during inflammatory shock syndromes when inactivation of PDC by increased PDK activity disrupts the tricarboxylic acid (TCA) cycle support of anabolic pathways. The transition from immune resistance to tolerance also diverts the TCA cycle from citrate‐derived cis‐aconitate to itaconate, a recently discovered catabolic mediator that separates the TCA cycle at isocitrate and succinate dehydrogenase (SDH). Itaconate inhibits succinate dehydrogenase and its anabolic role in mitochondrial ATP generation. We previously reported that inhibiting PDK in septic mice with dichloroacetate (DCA) increased TCA cycle activity, reversed septic shock, restored innate and adaptive immune and organ function, and increased survival. Here, using unbiased metabolomics in a monocyte culture model of severe acute inflammation that simulates sepsis reprogramming, we show that DCA‐induced activation of PDC restored anabolic energetics in inflammatory monocytes while increasing TCA cycle intermediates, decreasing itaconate, and increasing amino acid anaplerotic catabolism of branched‐chain amino acids (BCAAs). Our study provides new mechanistic insight that the DCA‐stimulated PDC homeostat reconfigures the TCA cycle and promotes anabolic energetics in monocytes by reducing levels of the catabolic mediator itaconate. It further supports the theory that PDC is an energy sensing and signaling homeostat that restores metabolic and energy fitness during acute inflammation.

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“…These findings indicate a negative feedback regulation after the activation of myeloid cells. The induction of itaconate followed by SDH inhibition also modulate the tolerance of myeloid cells and β-glucan can counteract the tolerance by inhibiting the expression of Irg1 [60].…”

Section: Krebs Cyclementioning

confidence: 99%

Metabolic Reprogramming in Mitochondria of Myeloid Cells

Zuo

Wan

2019

Cells

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The myeloid lineage consists of multiple immune cell types, such as macrophages, monocytes, and dendritic cells. It actively participates in both innate and adaptive immunity. In response to pro-or anti-inflammatory signals, these cells undergo distinct programmed metabolic changes especially in mitochondria. Pro-inflammatory signals induce not only a simple shift from oxidative phosphorylation to glycolysis, but also complicated metabolic alterations during the early and tolerant stages in myeloid cells. In mitochondria, a broken Krebs cycle leads to the accumulation of two metabolites, citrate and succinate, both of which trigger pro-inflammatory responses of myeloid cells. A deficient electron transport chain induces pro-inflammatory responses in the resting myeloid cells while it suppresses these responses in the polarized cells during inflammation. The metabolic reprogramming in mitochondria is also associated with altered mitochondrial morphology. On the other hand, intact oxidative phosphorylation is required for the anti-inflammatory functions of myeloid cells. Fatty acid synthesis is essential for the pro-inflammatory effect and glutamine metabolism in mitochondria exhibits the anti-inflammatory effect. A few aspects of metabolic reprogramming remain uncertain, for example, glycolysis and fatty acid oxidation in anti-inflammation. Overall, metabolic reprogramming is an important element of immune responses in myeloid cells.

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The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity

Cited by 252 publications

References 49 publications

Defining trained immunity and its role in health and disease

Defining trained immunity and its role in health and disease

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Metabolic Reprogramming in Mitochondria of Myeloid Cells

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