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

ABSTRACT: 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.

OTHER RELATED OMICS DATASETS IN: PRJNA434457PRJNA396951

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Marko Jovanovic

PROVIDER: MSV000082101 | MassIVE | Sun Feb 25 22:23:00 GMT 2018

REPOSITORIES: MassIVE

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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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