Deficiency of IRG1/ itaconate aggravates endotoxemia-induced acute lung injury by inhibiting autophagy in mice

作者全名："Qiu, Jing-Huan; Zhang, Li; LI, Ke-Xin; Zhang, Qiu-Hong; Fan, Ke-Rui; Chen, Kun; Jiang, Yu; Liu, Gang"

作者地址："[Qiu, Jing-Huan; Zhang, Qiu-Hong; Liu, Gang] Chongqing Med Univ, Dept Emergency & Crit Care Med, Univ Town Hosp, 55 Middle Rd, Chongqing 401331, Peoples R China; [Zhang, Li; Fan, Ke-Rui; Chen, Kun] Chongqing Med Univ, Dept Pathophysiol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [LI, Ke-Xin] Chongqing Med Univ, Univ Town Hosp, Med Sci Res Ctr, 55 Middle Rd, Chongqing 401331, Peoples R China; [Jiang, Yu] Chongqing Med Univ, Univ Town Hosp, Dept Resp & Crit Care Med, Middle Rd, Chongqing 401331, Peoples R China"

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

来源：EXPERIMENTAL ANIMALS

ESI学科分类：PLANT & ANIMAL SCIENCE

WOS号：WOS:000996167800003

JCR分区：Q1

影响因子：2.2

年份：2023

卷号：72

期号：2

开始页：164

结束页：172

文献类型：Article

关键词：acute lung injury; autophagy; inflammation; itaconate; metabolite

摘要："Itaconate, produced by aconitate decarboxylase 1 (ACOD1), which is encoded by immune-responsive gene 1 (Irg1), is one of the metabolites derived from the tricarboxylic acid cycle. It has been reported that exogenous itaconate plays an anti-inflammatory role in the progression of multiple diseases and pathological processes, including activated macrophage, ischemia-reperfusion injury, and acute lung injury. However, the role and specific mechanism of endogenous itaconate in endotoxemia-induced acute lung injury (ALI) remain unclear. The animal model of ALI in wild-type and Irg1(-/- )mice was constructed by LPS intraperitoneal injection. Ultrahigh-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) analysis was performed to measure the quantity of endogenous itaconate. The protective effect of itaconate was investigated by the behavioral assessment and the levels of inflammatory cytokines. Acute lung injury was assessed by hematoxylin and eosin staining, total protein in BALF, and Evans blue leakage. Western blotting was used to detect the IRG1 expression and autophagic protein in the lung. We demonstrated that IRG1 was highly expressed in ALI and that endogenous itaconate was produced simultaneously and was 100 times higher. Using Irg1(-/-) mice, we found that endogenous itaconate was likely to exert an anti-inflammatory effect by activating NRF2 and promoting autophagy. Furthermore, autophagy was restrained by LPS but enhanced by 4-octyl itaconate (4-OI) pretreatment. Our study illustrated that a deficiency of IRG1/Itaconate aggravates ALI and that the IRG1/itaconate pathway protects against ALI. The protective mechanisms could be related to the facilitation of autophagy. Such findings may provide a theoretical foundation for the treatment of endotoxemia-induced ALI."

基金机构："Natural Science Foundation of Chongqing [cstc2020jcyj-msxmX0254]; Chongqing Municipal Public Health Bureau of Chongqing People's Municipal Government [2022MSXM006]; Graduate Innovative Special Fund Projects of Chongqing [CYS20222, CYS21248]"

基金资助正文："This work was supported by grants from the Natural Science Foundation of Chongqing (No. cstc2020jcyj-msxmX0254) , Chongqing Municipal Public Health Bureau of Chongqing People's Municipal Government (2022MSXM006) , and Graduate Innovative Special Fund Projects of Chongqing (CYS20222; CYS21248) . We are very grateful to the College of Pharmacy, Chongqing Medical University, for its support."