<i>Irg1</i>/itaconate activates Nrf2/HO-1 pathway and mitigates septic liver injury in mice

作者全名："Zhang, Tingting; Li, Kexin; Qiu, Jinghuan; Zhang, Li; Wang, Xiaoliang; Zhang, Qiuhong; Qin, Yin; Liu, Jie; Liu, Gang"

作者地址："[Zhang, Tingting; Qiu, Jinghuan; Zhang, Qiuhong; Qin, Yin; Liu, Jie; Liu, Gang] Chongqing Med Univ, Univ Town Hosp, Dept Emergency & Crit Care Med, Chongqing, Peoples R China; [Zhang, Tingting; Li, Kexin; Wang, Xiaoliang; Liu, Gang] Chongqing Med Univ, Univ Town Hosp, Med Sci Res Ctr, Chongqing, Peoples R China; [Zhang, Li] Chongqing Med Univ, Dept Pathophysiol, Chongqing, Peoples R China; [Liu, Gang] Chongqing Med Univ, Univ Town Hosp, Dept Emergency & Crit Care Med, 55 Middle Rd, Chongqing 401331, Peoples R China"

通信作者："Liu, G (通讯作者)，Chongqing Med Univ, Univ Town Hosp, Dept Emergency & Crit Care Med, 55 Middle Rd, Chongqing 401331, Peoples R China."

来源：EUROPEAN JOURNAL OF INFLAMMATION

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001189098200001

JCR分区：Q4

影响因子：0.7

年份：2024

卷号：22

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Immune-responsive gene 1 (Irg1); itaconate; liver injury; nuclear erythroid 2-related factor 2 (Nrf2); sepsis

摘要："Objectives: Immune-responsive gene 1 (Irg1)-catalyzed production of itaconate is a bioactive metabolite with antibacterial, anti-inflammatory and antioxidant properties. Liver injury is closely related to poor outcomes in septic patients, while prevention of liver injury is essential for the pharmacological control of sepsis. This study investigated the pathological and pharmacological significance of Irg1/itaconate in septic liver injury. Methods: Septic liver injury was induced in mice by injecting lipopolysaccharide (LPS; 15 mg/kg) intraperitoneally. The hepatic mRNA and protein contents of Irg1 were detected. To investigate the pathological meaning of Irg1, septic liver injury was induced in Irg1 knockout mice and their wild-type (WT) littermates, and the degree of liver injury, hepatic inflammation, oxidative stress and the activation of nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) were subsequently determined. Finally, to explore the gene's pharmacological potential, 4-octyl itaconate (4-OI; 50 mg/kg), a derivative of itaconate that could cross cell membranes, was administered intraperitoneally. The mobilization of Nrf2/HO-1 and liver injury were then evaluated. Results: The level of Irg1 expression was dramatically enhanced in mice with septic liver injury. Additionally, Irg1 deletion leaded to higher ALT and AST levels, elevated inflammatory and oxidative-stress indicators and compromised stimulation of the Nrf2/HO-1 pathway. However, administering 4-OI restored the Nrf2/HO-1 pathway which mitigated liver injury and inhibited hepatic inflammation and oxidative stress. Conclusions: The results figured that elevation of Irg1 might be a protective event that control the progress of septic liver injury, while 4-OI might have latent significance for the pharmaceutical intervention of septic liver injury."

基金机构："Natural Science Foundation of Chongqing [cstc2020jcyj-msxmX0254, cstc2019jcyj-msxmX0294]; Graduate Innovative Special Fund Projects of Chongqing [CYS21248]; Chongqing Municipal Public Health Bureau of Chongqing People's Municipal Government [2022MSXM006]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN202000444]"

基金资助正文："The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Natural Science Foundation of Chongqing (grant no. cstc2020jcyj-msxmX0254; cstc2019jcyj-msxmX0294), the Graduate Innovative Special Fund Projects of Chongqing (grant no. CYS21248), the Chongqing Municipal Public Health Bureau of Chongqing People's Municipal Government (grant no. 2022MSXM006), and the Science and Technology Research Program of Chongqing Municipal Education Commission (KJQN202000444)."