4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112145
• Main Authors: Li, Weizhen, Li, Yangguang, Kang, Jiaqi, Jiang, Haiyang, Gong, Wenbin, Chen, Lijuan, Wu, Cunxia, Liu, Mingda, Wu, Xiuwen, Zhao, Yun, Ren, Jianan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2023; Elsevier
• Subjects: 4-OI; Alkylation; CLP; CP: Immunology; Humans; inflammation; Inflammation - drug therapy; IRG1; Itaconate; Membrane Proteins; metabolite; Proteins - metabolism; STING; Succinates - metabolism; Succinates - pharmacology; CP: Immunology; IRG1; Itaconate; metabolite; inflammation; CLP; STING; 4-OI
• DOI: 10.1016/j.celrep.2023.112145
• ISSN: 2211-1247

The Krebs cycle-derived metabolite itaconate, whose production is catalyzed by immune response gene 1 (IRG1), has potential to link immunity and metabolism in activated macrophages through alkylation or competitive inhibition of target proteins. In support of this, our previous study demonstrated that the stimulator of interferon genes (STING) signaling platform functions as a hub in macrophage immunity and has a profound impact on the prognosis of sepsis. Interestingly, we find that itaconate, an endogenous immunomodulator, can significantly inhibit the activation of STING signaling. Moreover, 4-octyl itaconate (4-OI), which is a permeable itaconate derivative, can alkylate cysteine sites 65, 71, 88, and 147 of STING, thereby inhibiting its phosphorylation. Furthermore, itaconate and 4-OI inhibit the production of inflammatory factors in sepsis models. Our results broaden the knowledge on the role of the IRG1-itaconate axis in immunomodulation and highlight itaconate and its derivatives as potential therapeutic agents in sepsis. [Display omitted] •Stimulating STING can promote the activation of IRG1-itaconate•4-OI alkylation modifies cysteine 147 of STING and inhibits STING phosphorylation•Itaconate and its derivative, 4-OI, down-regulate inflammation in mouse models of sepsis Li et al. reveal that the Krebs cycle-derived metabolite itaconate and its derivative, 4-OI, inhibit the phosphorylation of STING. Itaconate and its derivative, 4-OI, down-regulate inflammation in mouse sepsis, and 4-OI has potential as an alternative drug for sepsis treatment.