Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.
Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.
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衣康酸及其衍生物的亲电特性调控IκBζ - ATF3炎症轴。
DOI：
10.1038/s41586-018-0052-z
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发表时间：
2018-04
期刊：
影响因子：
64.8
通讯作者：
Artyomov MN
中科院分区：
文献类型：
--
作者：
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
代谢调节已被认为是指导免疫反应的一个强有力的原则。炎症巨噬细胞经历广泛的代谢重组，其标志是产生大量的衣康酸，衣康酸最近被描述为一种免疫调节代谢物。衣康酸及其膜透性衍生物衣康酸二甲酯(DI)选择性地抑制包括IL-6和IL-12在内的一组细胞因子，但不能抑制肿瘤坏死因子。衣康酸在巨噬细胞激活过程中对细胞代谢的主要影响被归因于对琥珀酸脱氢酶的抑制，然而这种抑制本身不足以解释在DI病例中观察到的显著的免疫调节作用。此外，衣康酸和去甲肾上腺素对炎症程序的选择性作用的调节途径还没有确定。在这里，我们表明衣康酸和DI诱导亲电应激，与谷胱甘肽反应，随后诱导Nrf2(也称为NFE2L2)依赖和非依赖的反应。我们发现，亲电应激可以通过抑制IκBζ蛋白的诱导来选择性地调节对Toll样受体刺激的次级转录反应，而不是初级转录反应。IκBζ的调节独立于NRF2，我们认为ATF3是其关键的调节因子。这种抑制作用在不同物种和细胞类型之间是保守的，体内给药DI可以改善由IL-17-IκBζ驱动的牛皮癣小鼠模型的皮肤病理，突出了这一调节途径的治疗潜力。我们的结果表明，靶向DI-IκBζ调节轴可能是治疗IL-17-IκBζ介导的自身免疫性疾病的重要新策略。
Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite. Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines, 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 dehydrogenase, 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.
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影响因子：
4.6
作者：
McGuire VA;Ruiz-Zorrilla Diez T;Emmerich CH;Strickson S;Ritorto MS;Sutavani RV;Weiβ A;Houslay KF;Knebel A;Meakin PJ;Phair IR;Ashford ML;Trost M;Arthur JS
通讯作者：
Arthur JS
Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
64.5
作者：
Cheng Z;Otto GM;Powers EN;Keskin A;Mertins P;Carr SA;Jovanovic M;Brar GA
通讯作者：
Brar GA
影响因子：
14.8
作者：
Rappsilber, Juri;Mann, Matthias;Ishihama, Yasushi
通讯作者：
Ishihama, Yasushi