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

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. Overall design: Bone marrow-derived macrophages (BMDMs) from WT and Nrf2–/– mice were derived in 7 days in MCSF supplemented complete RPMI. Some samples cells were stimulated with 250 uM DimethylItaconate(DI) for 12 hours prior to collection for RNA-seq.

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Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH, Duncan D, Bregman H, Keskin A, Santeford A, Apte RS, Sehgal R, Johnson B, Amarasinghe GK, Soares MP, Satoh T, Akira S, Hai T, de Guzman Strong C, Auclair K, Roddy TP, Biller SA, Jovanovic M, Klechevsky E, Stewart KM, Randolph GJ, Artyomov MN