Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response

Ryan, Dylan Gerard; Knatko, Elena V.; Casey, Alva M.; Hukelmann, Jens; Naidu, Sharadha Dayalan; Brenes, Alejandro; Ekkunagul, Thanapon; Baker, Christa; Higgins, Maureen; Tronci, Laura; Nikitopolou, Efterpi; Honda, Tadashi; Hartley, Richard C.; O’Neill, Luke A.J.; Frezza, Christian; Lamond, Angus I.; Abramov, Andrey Y.; Arthur, J. Simon C.; Cantrell, Doreen A.; Murphy, Michael P.; Dinkova‐Kostova, Albena T.

doi:10.1016/j.isci.2022.103827

Cited by 72 publications

(72 citation statements)

References 54 publications

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“…The transcription factor Nrf2 regulates the gene expression of about 250 target genes involved in redox regulation and antioxidant response, inflammation, heme and iron metabolism, intermediary lipid and carbohydrate metabolism, and reactions of detoxification and biotransformation [ 96 ]. An overwhelmingly broad spectrum of factors and cellular conditions that can regulate Nrf2 abundance and activity is known from preclinical studies [ 97 , 98 , 99 ]. On the contrary, the clinical data on Nrf2 abundance and activity in human CKD are scarce.…”

Section: Clinical Data Of Nrf2 Activation In Human Ckdmentioning

confidence: 99%

“…The TSUBAKI study also reported an increase in viral upper-respiratory-tract infections. The broad effect spectrum is not surprising, given the central role of Nrf2 in redox, protein and metabolic homeostasis as well as immune responses, and again considering the broad functional spectrum of Nrf2 targets such as NQO1 or HO-1 [ 96 , 99 , 120 , 167 ]. The comprehensive investigation of molecular and physiological responses that are/were elicited in this patient population during bardoxolone treatment is urgent.…”

Section: Clinical Data Of Nrf2 Activation In Human Ckdmentioning

confidence: 99%

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Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

et al. 2022

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The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a physiologic activity range. Oxidative stress and alterations in Nrf2-system activity are central for chronic-kidney-disease (CKD) progression and CKD-related morbidity. Activation of the Nrf2 system in CKD is in multiple ways related to inflammation, kidney fibrosis, and mitochondrial and metabolic effects. In human CKD, both endogenous Nrf2 activation and repression exist. The state of the Nrf2 system varies with the cause of kidney disease, comorbidities, stage of CKD, and severity of uremic toxin accumulation and inflammation. An earlier CKD stage, rapid progression of kidney disease, and inflammatory processes are associated with more robust Nrf2-system activation. Advanced CKD is associated with stronger Nrf2-system repression. Nrf2 activation is related to oxidative stress and moderate uremic toxin and nuclear factor kappa B (NF-κB) elevations. Nrf2 repression relates to high uremic toxin and NF-κB concentrations, and may be related to Kelch-like ECH-associated protein 1 (Keap1)-independent Nrf2 degradation. Furthermore, we review the effects of pharmacological Nrf2 activation by bardoxolone methyl, curcumin, and resveratrol in human CKD and outline strategies for how to adapt future Nrf2-targeted therapies to the requirements of patients with CKD.

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Section: Clinical Data Of Nrf2 Activation In Human Ckdmentioning

confidence: 99%

Section: Clinical Data Of Nrf2 Activation In Human Ckdmentioning

confidence: 99%

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

et al. 2022

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“…Studies have shown that Nrf2 protein levels in wild-type macrophages activated by LPS are higher than in macrophages with the deletion of the IRG1 gene, revealing that endogenous itaconate can induce Keap1/Nrf2 responses in macrophages. itaconate derivative 4-OI activates Nrf2 by Keap1 alkylation, inhibits certain pro-inflammatory cytokines in macrophages in vitro , and has a protective effect in LPS lethal models in vivo ( 26 ). Nrf2 can also activate the transcription of important macrophage function-related genes, such as macrophage receptors with collagen structures (MARCO), receptors needed for bacterial phagocytosis, differentiation cluster 36 (CD36), scavenger receptors that oxidized low-density lipoprotein(LDL), and viral monitoring mediator interleukin-17D (IL-17D) ( 26 ).…”

Section: Itaconate Activates Keap1/nrf2 To Regulate the Immune Functi...mentioning

confidence: 99%

“…itaconate derivative 4-OI activates Nrf2 by Keap1 alkylation, inhibits certain pro-inflammatory cytokines in macrophages in vitro , and has a protective effect in LPS lethal models in vivo ( 26 ). Nrf2 can also activate the transcription of important macrophage function-related genes, such as macrophage receptors with collagen structures (MARCO), receptors needed for bacterial phagocytosis, differentiation cluster 36 (CD36), scavenger receptors that oxidized low-density lipoprotein(LDL), and viral monitoring mediator interleukin-17D (IL-17D) ( 26 ). 4-OI activates Nrf2 via alkylating the cysteine of Keap1, which may be part of the reason for its anti-inflammatory effects.…”

Section: Itaconate Activates Keap1/nrf2 To Regulate the Immune Functi...mentioning

confidence: 99%

“…In addition, both activation and destruction of Nrf2 can lead to significant alterations in mitochondrial metabolites, such as those involved in fatty acid oxidation (FAO) (carnitine, palmitoyl carnitine, hexyl carnitine, and tetradecyl carnitine), TCA cycles (fumaric acid, malic acid, and 2-ketoglutaric acid), and bioenergy (NAD, creatine, creatine phosphate) ( 26 ). In stimulating these three types of cells with LPS, the antioxidant response and bioenergy-related metabolites increase significantly, and the abundance of several amino acids changes to varying degrees ( 26 ). These experimental data show that the derivative of itaconate, 4-OI, activates Keap1/Nrf2 to reduce oxidative stress to fight inflammation.…”

Section: Itaconate Activates Keap1/nrf2 To Regulate the Immune Functi...mentioning

confidence: 99%

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Research Progress on the Mechanism of Itaconate Regulating Macrophage Immunometabolism

Shi

Cai²

2022

Front. Immunol.

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The field of immunology is undergoing rapid and dramatic changes. Immunometabolism, a change in metabolic pathways within immune cells, is a key determinant in the activation of immune cells, and intermediates of immunometabolic processes which can influence inflammatory gene expression and play a role in inflammation. Itaconate is one of the most representative metabolites, produced in the tricarboxylic acid cycle (TCA cycle), which links macrophage metabolism, oxidative stress response and immune response to regulate macrophage activity, playing an important role in the function of macrophages. In this paper, we review the mechanisms of the metabolite itaconate and its derivatives in the regulation of macrophage immune metabolism, intending to gain further insight into the role and mechanisms of this metabolite in macrophages and provide new ideas for the mechanisms and treatment of clinical diseases.

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Nrf2 as a regulator of energy metabolism and mitochondrial function

Luchkova,

Mata,

Cadenas

2024

FEBS Letters

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Nuclear factor erythroid‐2‐related factor 2 (Nrf2) is essential for the control of cellular redox homeostasis. When activated, Nrf2 elicits cytoprotective effects through the expression of several genes encoding antioxidant and detoxifying enzymes. Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. Microarray and genome‐wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox‐regulatory capacity. Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. Nrf2 also modulates substrate utilization for mitochondrial respiration. Here we review the experimental evidence supporting the essential role of Nrf2 in the regulation of energy metabolism and mitochondrial function.

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Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response

Cited by 72 publications

References 54 publications

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

Research Progress on the Mechanism of Itaconate Regulating Macrophage Immunometabolism

Nrf2 as a regulator of energy metabolism and mitochondrial function

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