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

Monika Bambouskova, Laurent Gorvel, Vicky Lampropoulou, Alexey Sergushichev, Ekaterina Loginicheva, Kendall Johnson, Daniel Korenfeld, Mary Elizabeth Mathyer, Hyeryun Kim, Li-Hao Huang, Dustin Duncan, Howard Bregman, Abdurrahman Keskin, Andrea Santeford, Rajendra S. Apte, Raghav Sehgal, Britney Johnson, Gaya K. Amarasinghe, Miguel P. Soares, Takashi Satoh, Shizuo Akira, Tsonwin Hai, Cristina Guzman Strong, Karine Auclair, Thomas P. Roddy, Scott A. Biller, Marko Jovanovic, Eynav Klechevsky, Kelly M. Stewart, Gwendalyn J. Randolph and Maxim N. Artyomov ()
Additional contact information
Monika Bambouskova: Washington University School of Medicine
Laurent Gorvel: Washington University School of Medicine
Vicky Lampropoulou: Washington University School of Medicine
Alexey Sergushichev: ITMO University
Ekaterina Loginicheva: Washington University School of Medicine
Kendall Johnson: Agios Pharmaceuticals
Daniel Korenfeld: Washington University School of Medicine
Mary Elizabeth Mathyer: Washington University School of Medicine
Hyeryun Kim: Agios Pharmaceuticals
Li-Hao Huang: Washington University School of Medicine
Dustin Duncan: McGill University
Howard Bregman: Agios Pharmaceuticals
Abdurrahman Keskin: Columbia University
Andrea Santeford: Washington University School of Medicine
Rajendra S. Apte: Washington University School of Medicine
Raghav Sehgal: Elucidata Corporation
Britney Johnson: Washington University School of Medicine
Gaya K. Amarasinghe: Washington University School of Medicine
Miguel P. Soares: Instituto Gulbenkian de Ciência
Takashi Satoh: Osaka University
Shizuo Akira: Osaka University
Tsonwin Hai: Ohio State University
Cristina Guzman Strong: Washington University School of Medicine
Karine Auclair: McGill University
Thomas P. Roddy: Agios Pharmaceuticals
Scott A. Biller: Agios Pharmaceuticals
Marko Jovanovic: Columbia University
Eynav Klechevsky: Washington University School of Medicine
Kelly M. Stewart: Agios Pharmaceuticals
Gwendalyn J. Randolph: Washington University School of Medicine
Maxim N. Artyomov: Washington University School of Medicine

Nature, 2018, vol. 556, issue 7702, 501-504

Abstract: 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 IκBζ protein induction. The regulation of IκBζ 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–IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI–IκBζ regulatory axis could be an important new strategy for the treatment of IL-17–IκBζ-mediated autoimmune diseases.

Date: 2018
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DOI: 10.1038/s41586-018-0052-z

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