4-octyl itaconate as a metabolite derivative to inhibits cytokine-mediated inflammation via alkylation of TYK2 2258772

Abstract

Abstract Introduction Sepsis is a host’s dysregulated response to infection. Janus kinases and signal transduction factors and transcriptional activators (JAK-STATS) are among the most important signaling components downstream of cytokine receptors. This dysregulated host response includes the exacerbated systemic inflammatory response syndrome (SIRS) that occurs in an attempt to combat the invading pathogens. Itaconate, an anti-inflammatory metabolite synthesized by enzymes encoded by immune response gene 1 (IRG1). Itaconate and its derivatives are potent cysteine modifiers, due to its nature as an α,β-unsaturated dicarboxylic acid. Methods Through transcriptome and metabolite sequencing analysis of intestinal tissues obtained from CLP-induced mouse models. Cell experiments revealed that 4OI inhibited the JAK-STAT pathway.Through protein modification identification, explore the mechanism by which 4O regulates JAK-STAT. To explore the endogenous itaconate effect, IRG1 KO mice were constructed. To explore the role of the JAK-STAT pathway in sepsis, IFNAR1 KO and TYK2 KO mice were constructed. Results Our results suggest that endogenous itaconate is a negative regulator of type I interferon-mediated signaling pathway. 4OI inhibits the binding of TYK2 to IFNAR1 by alkylating the cysteine residue at position 192 of TYK2, and further negatively regulates the JAK-STAT pathway. To provide a theoretical basis for 4OI as a therapy for sepsis. Conclusion We find that itaconate, as a metabolite significantly up-regulated by metabolic reprogramming, can inhibit type I interferon signaling pathway. Exogenous supplementation of itaconate derivative 4OI can inhibit JAK-STAT pathway. Our research has identified the crucial role of itaconate produced by the tricarboxylic acid cycle in restricting JAK-STAT signal transduction, whose function is to connect metabolism and innate immunity and provided a theoretical basis for 4OI treatment of sepsis. Funding Source National Natural Science Foundation of China (82272209) Topic Categories Cytokines and Chemokines and their Receptors (CCR)