Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury

Cordes, Thekla; Lucas, Alfredo; Divakaruni, Ajit S.; Murphy, Anne N.; Cabrales, Pedro; Metallo, Christian M.

doi:10.1016/j.molmet.2019.11.019

Cited by 101 publications

(95 citation statements)

References 62 publications

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“…The TCA cycle starts by converting pyruvate, generated from the pentose phosphate pathway, glycolysis, or glycogen metabolism into acetyl-CoA, which then enters the TCA cycle [298]. Macrophage-based experiments and, to some extent, microglia-oriented research established that myeloid cells are able to switch their energy needs from an aerobic profile based on OxPhos and fatty acid oxidation (FAO) to a profile based on anaerobic profile utilizing glycolysis and the pentose phosphate pathway when exposed to pro-inflammatory stimuli [309][310][311][312]. In macrophages, several breakage points in the TCA cycle result in a significant switch in bioenergetics that allows for the signaling molecules itaconate, succinate, and citrate to escape from the mitochondria [313][314][315].…”

Section: Bioenergetics Of Microglia: a Phenotypic Energy Switchmentioning

confidence: 99%

“…Past research has shown that SDH is responsible for driving cellular metabolism towards the generation of ROS, thus connecting the metabolite itaconate through its inhibition of the enzymatic activity of SDH by blocking its active site, to oxidative stress [311].…”

Section: Bioenergetics Of Microglia: a Phenotypic Energy Switchmentioning

confidence: 99%

“…Accumulated citrate, on the other hand, is transported out of the mitochondria and utilized for synthesis of fatty acids, generation of NO, and prostaglandins [318]. In a recent study by Cordes and colleagues, exogenous itaconate treatment was tested in primary rat cortical neurons and astrocytes showing that itaconate acts as a mitochondrial regulator that controls redox metabolism and further connects to glutathione metabolism [311]. Nevertheless, the findings concerning itaconate and its significant regulatory roles in macrophages call out for further investigation in microglia in order to understand if similar regulatory functions related to energy metabolism occur and may be a potential target in microglia.…”

Section: Bioenergetics Of Microglia: a Phenotypic Energy Switchmentioning

confidence: 99%

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Microglia: Agents of the CNS Pro-Inflammatory Response

Rodríguez‐Gómez

Kavanagh

Engskog-Vlachos

et al. 2020

Cells

207

153

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The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

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Section: Bioenergetics Of Microglia: a Phenotypic Energy Switchmentioning

confidence: 99%

Section: Bioenergetics Of Microglia: a Phenotypic Energy Switchmentioning

confidence: 99%

Section: Bioenergetics Of Microglia: a Phenotypic Energy Switchmentioning

confidence: 99%

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Microglia: Agents of the CNS Pro-Inflammatory Response

Rodríguez‐Gómez

Kavanagh

Engskog-Vlachos

et al. 2020

Cells

207

153

View full text Add to dashboard Cite

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“…Whereas itaconate was recently demonstrated to have a complex immunomodulatory effect on mammalian cells(3, 4) (e.g. inhibition of succinate dehydrogenase,(5) downregulation of glycolysis, (6) programming macrophages for communication to other leukocytes, (7) and other immunoregulatory effects (8)(9)(10)(11)(12)), other reports have suggested that itaconate produced by macrophages may contribute to the antimicrobial activity of the innate immune system. (2,13) Consistent with the latter role, an itaconate degradation pathway has been identified in some bacterial species known to proliferate in macrophages.…”

Section: Figure 1: Within Macrophages Diversion Of the Citric Acid Cmentioning

confidence: 99%

The antimicrobial activity of the macrophage metabolite itaconate is synergistic with acidity

Duncan

Lupien

Behr

et al. 2020

Preprint

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The production of itaconate by macrophages was only discovered in 2011. A rapidly increasing number of studies have since revealed essential biological roles for itaconate, ranging from antimicrobial to immunomodulator. Itaconate has been estimated to reach low-millimolar concentrations in activated macrophages, including those within infected lungs and brains, whereas itaconate’s MIC towards several bacterial strains were measured to be in the low-to-mid-millimolar range, casting some doubts on the antibacterial role of itaconate in vivo. Several of these investigations, in particular those measuring MIC values of itaconate or itaconic acid, have however tended to ignore the high acidity of this small diacid (pKas 3.85 and 5.45), thereby potentially biasing the MIC measurements. We report herein that: 1) at high concentration, itaconic acid can significantly reduce the pH of growth media; 2) the antibacterial activity of itaconate increases in a synergistic manner with acidity; 3) this synergistic effect is not simply due to increased permeability of monoanionic itaconate; 4) considering that the MIC of itaconate is many fold lower under acidic conditions for all strains tested, itaconate may serve an antimicrobial role, particularly in acidic vesicles such as the phagolysosome; and 5) differential growth behavior in the presence of disodium itaconate versus itaconic acid may serve to rapidly screen bacterial strains for their ability to metabolize itaconate. Our results further support the hypothesis that inhibitors of itaconate degradation in bacteria may provide a new strategy to treat infections.

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“…Furthermore, dimethyl itaconate (DMI), an itaconate derivative, was reported to inhibit IL- 17-induced IκBς activation in keratinocytes and ameliorate disease severity in the imiquimod-induced psoriasis animal model (9). Moreover, DMI was shown to offer a protection against myocardial and cerebral ischemic/reperfusion injury in animal models (10,11). Finally, DMI was recently reported by our group to suppress neuroin ammation and ameliorate disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (12).…”

Section: Introductionmentioning

confidence: 99%

Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

Kuo¹,

Weng²,

Scofield³

et al. 2020

Preprint

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Background Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of IRG1/itaconate axis has recently documented in LPS-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether IRG1/itaconate axis exerts an immunomodulatory effect in ischemic stroke is unknown. Thus, we investigated whether IRG1 plays a role in modulating brain injury in ischemic stroke. In addition, the molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke were elucidated. Methods Wild type (WT) C57BL/6 and IRG1−/− mice were subjected to 40 minutes middle cerebral artery occlusion (MCAO). Ischemic brain injury, microglia (MG) activation and peripheral immune cell infiltration of the ischemic brain were assessed. Furthermore, the expression of HO-1 and BDNF in the ischemic brain was measured. Finally, IRG1−/− MCAO mice were administered with D3T, an Nrf2/HO-1 pathway inducer, to determine its effects on cerebral BDNF expression and ischemic brain injury. Results We observed IRG1 was highly induced in the ischemic brain of WT but not IRG1−/− MCAO mice. Strikingly, IRG1−/− MCAO mice exhibited exacerbated brain injury with enlarged cerebral infarct, enhanced MG activation, and elevated immune cell infiltrates compared to WT MCAO controls. Further analysis of molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke revealed that IRG1 promoted HO-1 and BDNF expression to restrain ischemic brain injury, as IRG1−/− MCAO mice exhibited reduced HO-1 and BDNF expression in the ischemic brain compared to WT MCAO controls. Notably, D3T, an Nrf2/HO-1 pathway inducer, promoted BDNF expression and lessened ischemic brain injury in IRG1−/− MCAO mice. Conclusions We demonstrate that the induction of IRG1 following ischemic stroke may serve as an endogenous protective mechanism to restrain ischemic brain injury, and that may be mediated through the protective effect of IRG1 on the induction of HO-1 and BDNF expression in the ischemic brain. Thus, our study suggests that targeting IRG1 may represent a novel approach for the treatment of ischemic stroke.

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Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury

Cited by 101 publications

References 62 publications

Microglia: Agents of the CNS Pro-Inflammatory Response

Microglia: Agents of the CNS Pro-Inflammatory Response

The antimicrobial activity of the macrophage metabolite itaconate is synergistic with acidity

Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

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