Dimethyl itaconate induces long-term innate immune responses and confers protection against infection

Ferreira, Anaísa V; Kostidis, Sarantos; Groh, Laszlo; Koeken, Valerie A C M; Bruno, Mariolina; Baydemir, İlayda; Kılıç, Gizem; Bulut, Özlem; Andriopoulou, Theano; Spanou, Victoria M; Synodinou, Kalliopi D.; Gkavogianni, Theologia; Moorlag, Simone J.C.F.M.; Bree, L. Charlotte de; Mourits, Vera P.; Matzaraki, Vasiliki; Koopman, Werner J.H.; Veerdonk, Frank L. van de; Renieris, Georgios; Giera, Martin; Giamarellos‐Bourboulis, Evangelos J.; Novakovic, Boris; Domínguez‐Andrés, Jorge

doi:10.1016/j.celrep.2023.112658

Cited by 13 publications

(3 citation statements)

References 52 publications

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“…who found inhibition of LPS-induced ACOD1 expression by β-glucan in human monocytes, that was accompanied by a restoration of SDH expression and TCA cycle metabolites, and resulted in reversal of cytokine production ( 75 ). In a recent follow-up study, the same group reported that pre-treatment of human monocytes with DMI in a trained immunity-protocol increased cytokine production to secondary TLR stimulation ( 76 ). This effect was more pronounced for DMI than for itaconate, but still indicates that the ACOD1-itaconate axis can enhance innate immune responses under certain conditions.…”

Section: Effects Of Itaconate On Immune Responsesmentioning

confidence: 99%

Control of immune cell signaling by the immuno-metabolite itaconate

Lang,

Siddique

2024

Front. Immunol.

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Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell’s metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.

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Section: Effects Of Itaconate On Immune Responsesmentioning

confidence: 99%

Control of immune cell signaling by the immuno-metabolite itaconate

Lang,

Siddique

2024

Front. Immunol.

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“…This process can be counteracted by treatment with the fungal cell wall component β-glucan, which reduces IRG1 expression and itaconate accumulation, in a process called trained immunity [ 83 ]. Conversely, DMI, in the absence of other stimuli, can actually increase the responsiveness of human monocytes to secondary stimulation with LPS by increasing ROS production, and it also protected mice from secondary infection with Staphylococcus aureus [ 84 ].…”

Section: Introductionmentioning

confidence: 99%

Basic Mechanisms of Immunometabolites in Shaping the Immune Response

Ryan,

Peace,

Hooftman

2023

J Innate Immun

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Background: Innate immune cells play a crucial role in responding to microbial infections, but their improper activation can also drive inflammatory disease. For this reason, their activation state is governed by a multitude of factors, including the metabolic state of the cell and, more specifically, the individual metabolites which accumulate intracellularly and extracellularly. This relationship is bidirectional, as innate immune cell activation by pathogen-associated molecular patterns causes critical changes in cellular metabolism. Summary: In this review, we describe the emergence of various “immunometabolites.” We outline the general characteristics of these immunometabolites, the conditions under which they accumulate, and their subsequent impact on immune cells. We delve into well-studied metabolites of recent years, such as succinate and itaconate, as well as newly emerging immunometabolites, such as methylglyoxal. Key Messages: We hope that this review may be used as a framework for further studies dissecting the mechanisms by which immunometabolites regulate the immune system and provide an outlook to harnessing these mechanisms in the treatment of inflammatory diseases.

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“…Training induces metabolic and epigenetic changes within innate immune cells (including macrophages, neutrophils, and natural killer cells) as well as non-immune cells (such as fibroblasts, intestinal stromal cells, and epithelial stem cells) that typically result in a heightened response to a secondary challenge ( Hamada et al, 2019 ; Netea et al, 2020 ). Trained immunity has been induced by a range of stimuli including vaccines ( Kleinnijenhuis et al, 2012 ; Arts et al, 2018 ; Kaufmann et al, 2018 ), metabolites ( Arts et al, 2016 ; Ferreira et al, 2023 ), and fungal polysaccharides such as β-glucan ( Arts et al, 2016 ; Mitroulis et al, 2018 ; Kalafati et al, 2020 ). Trained immunity has been largely studied in vitro or following ex vivo re-stimulation of cells extracted from trained mice, adult zebrafish, or humans ( Kleinnijenhuis et al, 2012 ; Kaufmann et al, 2018 ; Rodríguez et al, 2009 ; Megías et al, 2016 ; Arts et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Microinjection of β-glucan Into Larval Zebrafish (Danio rerio) for the Assessment of a Trained-Like Immunity Phenotype

Darroch,

Astin,

Hall

2023

BIO-PROTOCOL

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The innate immune system can remember previous inflammatory insults, enabling long-term heightened responsiveness to secondary immune challenges in a process termed “trained immunity.” Trained innate immune cells undergo metabolic and epigenetic remodelling and, upon a secondary challenge, provide enhanced protection with therapeutic potential. Trained immunity has largely been studied in innate immune cells in vitro or following ex vivo re-stimulation where the primary insult is typically injected into a mouse, adult zebrafish, or human. While highly informative, there is an opportunity to investigate trained immunity entirely in vivo within an unperturbed, intact whole organism. The exclusively innate immune response of larval zebrafish offers an attractive system to model trained immunity. Larval zebrafish have a functional innate immune system by 2 days post fertilisation (dpf) and are amenable to high-resolution, high-throughput analysis. This, combined with their optical transparency, conserved antibacterial responses, and availability of transgenic reporter lines, makes them an attractive alternative model to study trained immunity in vivo. We have devised a protocol where β-glucan (one of the most widely used experimental triggers of trained immunity) is systemically delivered into larval zebrafish using microinjection to stimulate a trained-like phenotype. Following stimulation, larvae are assessed for changes in gene expression, which indicate the stimulatory effect of β-glucan. This protocol describes a robust delivery method of one of the gold standard stimulators of trained immunity into a model organism that is highly amenable to several non-invasive downstream analyses. Key features • This protocol outlines the delivery of one of the most common experimental stimulators of trained immunity into larval zebrafish. • The protocol enables the assessment of a trained-like phenotype in vivo. • This protocol can be applied to transgenic or mutant zebrafish lines to investigate cells or genes of interest in response to β-glucan stimulation.

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Dimethyl itaconate induces long-term innate immune responses and confers protection against infection

Cited by 13 publications

References 52 publications

Control of immune cell signaling by the immuno-metabolite itaconate

Control of immune cell signaling by the immuno-metabolite itaconate

Basic Mechanisms of Immunometabolites in Shaping the Immune Response

Microinjection of β-glucan Into Larval Zebrafish (<em>Danio rerio</em>) for the Assessment of a Trained-Like Immunity Phenotype

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