Title: IRG1-Itaconate axis inhibits SYK kinase by negative feedback and restores hvKP- induced intestinal homeostatic imbalance
Abstract:
Highly virulent Klebsiella pneumoniae (hvKP) is a severely life-threatening opportunistic pathogen that is spreading globally. It is necessary to discover the host response initiated by hvKP and then implement targeted interventions. Our previous studies have concluded that itaconate, an endogenous TCA cycle-related metabolite catalyzed by immune response gene 1 (IRG1), serves as a vital node for regulating macrophage immune metabolism. Our study discovered an interaction between the metabolic center represented by the IRG1-itaconate axis and the excessive inflammatory pathway mediated by SYK in the host immune response. HvKP could markedly disturb TCA cycle metabolism, represented by the significant upregulation of the IRG1-itaconate axis. Of note, this metabolic alteration requires the activation of spleen tyrosine kinase (SYK), which is a key signaling molecule in the immune response. Furthermore, Itaconate, generated after SYK activation, can alkylate the kinase domain of SYK to ameliorate excessive inflammation. The SYK-IRG1-Itaconate immunometabolism regulatory axis might be an treatment opportunity in hvKP infection. HvKP causes intestinal homeostasis imbalance to induce multisystem infection. Furthermore, we demonstrated that itaconate and its derivatives alleviate hvKP-mediated intestinal homeostasis imbalance and fatal injury. Our findings would broaden the understanding of immunological and metabolic disorders in the host response and likely yield insights into itaconate treatment opportunities against hvKP infection.
Biography:
Yun Zhao has completed his PhD at the age of 33 years from Third Millitary Medical University. He is the director of Medical Research Center for Surgical Infection and Immunology, The Nanjing Medical University. He has published over 50 papers in reputed journals and has been serving as an editorial board member
