Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

Mills, Evanna L.; Ryan, Dylan Gerard; Prag, Hiran A.; Dikovskaya, Dina; Menon, Deepthi; Zasłona, Zbigniew; Jedrychowski, Mark P.; Costa, Ana S.H.; Higgins, Maureen; Hams, Emily; Szpyt, John; Runtsch, Marah C.; King, Martin S.; McGouran, Joanna F.; Fischer, Román; Kessler, Benedikt M.; McGettrick, Anne F.; Hughes, Mark; Carroll, Richard G.; Booty, Lee M.; Knatko, Elena V.; Meakin, Paul J.; Ashford, M. L. J.; Modis, Louise K.; Brunori, Gino; Sévin, Daniel C.; Fallon, Padraic G.; Caldwell, Stuart T.; Kunji, Edmund R. S.; Chouchani, Edward T.; Frezza, Christian; Dinkova‐Kostova, Albena T.; Hartley, Richard C.; Murphy, Michael P.; O’Neill, Luke A. J.

doi:10.1038/nature25986

Cited by 1,319 publications

(1,632 citation statements)

References 30 publications

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“…Chemicals, reagents and antibodies OI was synthesized by Min-de Biotech (Suzhou, China) based on a previously described protocol [16]. Lipopolysaccharide (LPS) and puromycin were purchased from Sigma-Aldrich Co. (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

“…We first tested the potential effect of OI, the cell-permeable derivative of itaconate [16], on Nrf2 signaling in THP-1 human macrophages [31,32]. By performing the coimmunoprecipitation assay, we showed that treatment with OI (25 μM, 2 h) disrupted the association between Keap1-Nrf2 in THP-1 cells (Fig.…”

Section: Oi Activated Nrf2 Signaling In Thp-1 Cells and Sle Patient-dmentioning

confidence: 99%

“…The detailed protocol has been described previously [16]. In brief, the inducer potency was quantified by use of the NQO1 bioassay.…”

Section: Nqo1 Activity Assaymentioning

confidence: 99%

“…A recent study by Mills et al demonstrated that itaconate is a novel activator of Nrf2 [16]. Itaconate directly alkylates cysteine residues 151, 257, 288, 273, and 297 on Keap1, causing Nrf2 protein stabilization, accumulation, and activation [16].…”

Section: Introductionmentioning

confidence: 99%

“…Itaconate directly alkylates cysteine residues 151, 257, 288, 273, and 297 on Keap1, causing Nrf2 protein stabilization, accumulation, and activation [16]. Additionally, a new cell-permeable itaconate derivative, 4-octyl itaconate (OI), increases the expression of Nrf2 downstream genes with antioxidant and anti-inflammatory capacities [16].…”

Section: Introductionmentioning

confidence: 99%

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4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

Tang¹,

Wang²,

Xie³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.

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Section: Methodsmentioning

confidence: 99%

Section: Oi Activated Nrf2 Signaling In Thp-1 Cells and Sle Patient-dmentioning

confidence: 99%

“…The detailed protocol has been described previously [16]. In brief, the inducer potency was quantified by use of the NQO1 bioassay.…”

Section: Nqo1 Activity Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

Tang¹,

Wang²,

Xie³

et al. 2018

Cell Physiol Biochem

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Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

2022

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Regulation of cellular catabolic metabolism in immune cells has recently become a major concept for resolution of inflammation. Nuclear receptors (NRs), including peroxisome proliferator activator receptors, 1,25‐dihydroxyvitamin D (3) receptor, liver X receptors, glucocorticoid receptors, oestrogen‐related receptor α and nuclear receptor 4A1, have been identified as major modulators of inflammation, affecting innate immune cells, such as macrophages. Evidence emerges on how NRs regulate cellular metabolism in macrophages during inflammatory processes and contribute to the resolution of inflammation. This could have new implications for our understanding of how NRs shape immune responses and inform anti‐inflammatory drug design. This review will highlight the recent developments about NRs and their role in cellular metabolism in macrophages.

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Elucidating tumour‐associated microglia/macrophage diversity along glioblastoma progression and underACOD1deficiency

et al. 2022

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In glioblastoma (GBM), tumour-associated microglia/macrophages (TAMs) represent the major cell type of the stromal compartment and contribute to tumour immune escape mechanisms. Thus, targeting TAMs is emerging as a promising strategy for immunotherapy. However, TAM heterogeneity and metabolic adaptation along GBM progression represent critical features for the design of effective TAM-targeted therapies. Here, we comprehensively study the cellular and molecular changes of TAMs in the GL261 GBM mouse model, combining single-cell RNA-sequencing with flow cytometry and immunohistological analyses along GBM progression and in the absence of Acod1 (also known as Irg1), a key gene involved in the metabolic reprogramming of macrophages towards an anti-inflammatory phenotype. Similarly to patients, we identify distinct TAM profiles, mainly based on their ontogeny, that reiterate the idea that microglia-and macrophage-like cells show key transcriptional differences and dynamically adapt along GBM stages. Notably, we uncover decreased antigen-presenting cell features and immune reactivity in TAMs along tumour progression that are instead enhanced in Acod1-deficient mice. Overall, our results provide insight into TAM heterogeneity and highlight a novel role for Acod1 in TAM adaptation during GBM progression.

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Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

Cited by 1,319 publications

References 30 publications

4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

Elucidating tumour‐associated microglia/macrophage diversity along glioblastoma progression and underACOD1deficiency

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