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Electrophilic stress induced by dimethyl itaconate regulates IkB-zeta-mediated inflammatory responses

ABSTRACT: Interplay between metabolic state of the cell and its ability to undergo immunological activation has been recently recognized as a treasure chest of novel fundamental regulatory principles. Itaconate, and its membrane permeable derivative dimethyl itaconate (DI) were recently shown to selectively inhibit subset of cytokines during macrophage activation (e.g. Il1b, il6, Il12b but not TNF), yet the precise mechanism of this effect remained unclear. We find that selectivity of DI action stems from the inhibitory effects of electrophilic stress exerted by DI on IkB-zeta protein translation, leading to selective control of the secondary wave of Nfkb-signaling. Mechanistically, DI leads to glutathione depletion and subsequent activation of both Nrf2-dependent and Nrf2-independent stress responses. We find that IkB-zeta regulation is carried out in Nrf2-independent manner, and identify Atf3 as a key mediator of DI effects on IkB-zeta/IL6. This inhibitory effect is conserved across species and cell types, as evident from inhibition of IkB-zeta production in activating human monocytes and IL-17A stimulated keratinocytes of both human and mice. Finally, DI administration in vivo ameliorated IL17/IkB-zeta-driven skin pathology in the mouse model of psoriasis, highlighting therapeutic potential of this regulatory pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE102190 | GEO | 2018/04/21

REPOSITORIES: GEO

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Electrophilic stress induced by itaconate and its derivatives regulates ATF3-IKBZ inflammatory axis independently of Nrf2 induction

Project description:Metabolic regulation recently emerged as a novel powerful principle guiding immune responses. The natural metabolite itaconate and its membrane permeable derivative dimethyl itaconate (DI) were recently shown to selectively inhibit a subset of cytokines during macrophage activation, yet the precise mechanism of this effect remained unclear. We show here that itaconate/DI react with glutathione and subsequently induce both Nrf2-dependent and Nrf2-independent stress responses. We find that the striking selectivity of DI action stems from the inhibitory effects of electrophilic stress on IKBZ protein translation, leading to the inhibition of only the secondary wave of NF-KB signaling. We find that IKBZ regulation occurs in an Nrf2-independent manner, and identify ATF3 as a key mediator of the immunosuppression.

2018-02-25 | MSV000082101 | MassIVE

Dimethyl itaconate inhibits secondary wave of NF-κB signaling in macrophage activation

Project description:Natural metabolite itaconate and its membrane permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines during macrophage activation (e.g. IL-1β, IL-6, IL-12 but not TNF-α). Selectivity of DI action stems from the inhibitory effects of secondary, but not primary, wave of NF-κB signaling.

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Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1Î²-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.

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Project description:Electrophilic stress induced by dimethyl itaconate regulates IkB-zeta-mediated inflammatory responses

| PRJNA396951 | ENA

Histone marks in C. elegans IKB mutants

Project description:Our study focuses in undersatnding the chromatin-associated function of the c. elegans IKB homologues nfki-1 and ikb-1. We this objective, we have generated different worm mutant strains and then analyzed by ChIP-seq possible changes in H3K36me3 and H3K27me3 marks in the WT , nfki-1, ikb-1 and double c elegans mutants.

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Dimethyl Itaconate selectively targets chronic lymphocytic leukemia cells

Project description:Chronic Lymphocytic Leukemia (CLL) is strictly dependent on the complex interplay between the intrinsic features of the leukemic cells and microenvironmental stimulations including inflammatory stimuli by Toll Like Receptors (TLR) which protect CLL cells from drug induced apoptosis by upregulating NFKBIZ, an atypical co-transcription factor. To face the challenge of targeting transcription factors, we exploited the capacity of Dimethyl Itaconate (DI), an electrophilic synthetic derivative of Itaconate, to block NFKBIZ acting as anti-inflammatory agent. Primary CLL cells isolated from the peripheral blood of patients, leukemic splenocytes isolated from TCL1 transgenic mice, and circulating leukocytes isolated from healthy donors were treated in vitro with increasing concentrations of DI either alone or in combination with the TLR ligands. DI abrogated the induction of NFKBIZ as well as its target genes IL6 and IL10. Remarkably, DI reduced metabolic activation and cell viability of leukemic cells even if added after a robust TLR pre-stimulation; in contrast, no toxic effect was evident in normal leukocytes including T- and B-lymphocytes. DI induced apoptosis of malignant cells by reducing BCL-XL and MCL1 levels while inducing PARP cleavage. RNA sequencing highlighted that DI abrogated the TLR9-mediated upregulation of transcripts related to the metabolism of rRNAs, interferon and cytokine signaling. Notably, in addition to the expected electrophilic stress signature observed after DI treatment, novel pathways emerged including the downregulation of distinct MHC class II complex genes. In conclusion, DI not only abrogated the pro-inflammatory effects of TLR stimulation but also targeted a specific vulnerability in CLL cells.

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Dimethyl Itaconate selectively targets chronic lymphocytic leukemia cells

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Comparative evaluation of metabolic, electrophilic, and immunologic effects of itaconate and its ester derivatives on macrophage activation

Project description:Itaconate is a metabolite naturally produced in large amounts in macrophages after exposure to immune stimulation. Following the discovery of itaconate’s immunoregulatory properties, several ester derivatives of this dicarboxylic acid were designed to further examine its role. We evaluated the metabolic, electrophilic, and immunologic profiles of macrophages treated with unmodified itaconate and a panel of itaconate derivatives. We found that only unmodified itaconate strongly enhances LPS-induced IFNb secretion after 12h pre-treatment. Thus, we compared the transcriptional profile of wild type and Irg1-/- cells, which are unable to produce itaconate, after 24h LPS stimulation. We find that cells lacking itaconate have impaired downstream type I interferon signaling, and that addition of itaconate Irg1-/- BMDMs restores this signaling back to levels comparable to wild type. This data highlights the role of itaconate as an immunoregulatory metabolite, and highlights the importance of using unmodified itaconate or genetic knockout models in future mechanistic studies.

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Dimethyl Itaconate alleviates the pyroptosis of macrophages through oxidative stress

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