Sepsis is a
multiple organ dysfunction syndrome due to a dysregulated response to
infection with unacceptably high mortality. Currently, no effective treatment exists for
sepsis. IRG1/
itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/
itaconate on
lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced
sepsis model was used. IRG1-/- and wild type mice were used to explore the protective role of IRG1/
itaconate on multi-organ injury. GSDMD-/- mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially
lung injury.
4-Octyl itaconate (4-OI), a derivative of
itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1β (IL-1β),
IL-6,
tumor necrosis factor-α (TNF-α) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/
itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited
nuclear factor-kappaB/
mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD-/- mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated
lung injury. In conclusion, our data demonstrated that IRG1/
itaconate protect against multi-organ injury via inhibiting
inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against
sepsis.