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

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, 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 WT 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 levels of inflammatory cytokines. Acute lung injury was assessed by H&E staining, 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 endogenous itaconate was produced simultaneously and up to 100 times. 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 the deficiency of IRG1/Itaconate aggravates ALI and the IRG1/Itaconate pathway protects against ALI. The protective mechanisms could be related to facilitate autophagy. Such findings may provide a theoretical foundation for endotoxemia-induced ALI treatment.