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Electrophilic properties of itaconate and derivatives regulate the I?B?-ATF3 inflammatory axis.

ABSTRACT: Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of I?B? protein induction. The regulation of I?B? is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-I?B?-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-I?B? regulatory axis could be an important new strategy for the treatment of IL-17-I?B?-mediated autoimmune diseases.

SUBMITTER: Bambouskova M

PROVIDER: S-EPMC6037913 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.

Bambouskova Monika M Gorvel Laurent L Lampropoulou Vicky V Sergushichev Alexey A Loginicheva Ekaterina E Johnson Kendall K Korenfeld Daniel D Mathyer Mary Elizabeth ME Kim Hyeryun H Huang Li-Hao LH Duncan Dustin D Bregman Howard H Keskin Abdurrahman A Santeford Andrea A Apte Rajendra S RS Sehgal Raghav R Johnson Britney B Amarasinghe Gaya K GK Soares Miguel P MP Satoh Takashi T Akira Shizuo S Hai Tsonwin T de Guzman Strong Cristina C Auclair Karine K Roddy Thomas P TP Biller Scott A SA Jovanovic Marko M Klechevsky Eynav E Stewart Kelly M KM Randolph Gwendalyn J GJ Artyomov Maxim N MN

Nature 20180418 7702

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of i ...[more]

PMID: 29670287

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Project description:UnlabelledDietary ω-3 polyunsaturated fatty acids (PUFAs) decrease cardiovascular risk via suppression of inflammation. The generation of electrophilic α,β-unsaturated ketone derivatives of the ω-3 PUFAs docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) in activated human macrophages is catalyzed by cyclooxygenase-2 (Cox-2). These derivatives are potent pleiotropic anti-inflammatory signaling mediators that act via mechanisms including the activation of Nrf2-dependent phase 2 gene expression and suppression of pro-inflammatory NF-κB-driven gene expression. Herein, the endogenous generation of ω-3 PUFAs electrophilic ketone derivatives and their hydroxy precursors was evaluated in human neutrophils. In addition, their dietary modulation was assessed through a randomized clinical trial.MethodsEndogenous generation of electrophilic omega-3 PUFAs and their hydroxy precursors was evaluated by mass spectrometry in neutrophils isolated from healthy subjects, both at baseline and upon stimulation with calcium ionophore. For the clinical trial, participants were healthy adults 30-55 years of age with a reported EPA+DHA consumption of ≤300 mg/day randomly assigned to parallel groups receiving daily oil capsule supplements for a period of 4 months containing either 1.4 g of EPA+DHA (active condition, n = 24) or identical appearing soybean oil (control condition, n = 21). Participants and laboratory technicians remained blinded to treatment assignments.Results5-lypoxygenase-dependent endogenous generation of 7-oxo-DHA, 7-oxo-DPA and 5-oxo-EPA and their hydroxy precursors is reported in human neutrophils stimulated with calcium ionophore and phorbol 12-myristate 13-acetate (PMA). Dietary EPA+DHA supplementation significantly increased the formation of 7-oxo-DHA and 5-oxo-EPA, with no significant modulation of arachidonic acid (AA) metabolite levels.ConclusionsThe endogenous detection of these electrophilic ω-3 fatty acid ketone derivatives supports the precept that the benefit of ω-3 PUFA-rich diets can be attributed to the generation of electrophilic oxygenated metabolites that transduce anti-inflammatory actions rather than the suppression of pro-inflammatory AA metabolites.Trial registrationClinicalTrials.gov NCT00663871.

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Electrophilic properties of itaconate and derivatives regulate the I?B?-ATF3 inflammatory axis.

Publications

Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.

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