Irisin protects against sepsis-associated encephalopathy by suppressing ferroptosis via activation of the Nrf2/GPX4 signal axis

Sepsis-associated encephalopathy (SAE) is a common complication of severe sepsis. Irisin is a novel exercise induced myokine involved in the regulation of adipose browning and thermogenesis. This study is designed to verify the existence of ferroptosis in the pathogenesis of SAE and demonstrate that irisin attenuated cognitive dysfunction in SAE mice via inhibition of hippocampus ferroptosis. A mouse SAE model was induced by cecal ligation and puncture (CLP) and in vitro model was established by LPS-stimulated hippocampus cells. Irisin were pre-treated in the models. We found that SAE triggered hippocampus ferroptosis, as evidenced by increasing ROS, iron content and MDA and reducing GSH level as well as altered ferroptosis-related protein (GPX4, ACSL4 and SLC7A11) expression, whereas irisin attenuated CLP-induced learning and memory dysfunction, neurologic severity score and hippocampus ferroptosis and microglial activation in SAE mice. However, the protective effect of irisin was eliminated by ferroptosis inducer Erastin. Consistently, irisin reduced ferroptosis and improved mitochondrial dysfunction in LPS-induced HT-22 cells, as evidenced by decreased lipid ROS and increased mitochondrial membrane potential. Furthermore, proteomics identified the differentially expressed proteins linked to ferroptosis in SAE. We also observed that irisin-mediated anti-ferroptosis was abolished by siRNA-Nrf2 or in Nrf2-/-mice. Transwell assay revealed that irisin could prevent the recruitment and chemotaxis of microglial cells induced by ferroptotic hippocampal cells. In conclusion, irisin could ameliorate inflammatory microenvironment in SAE by suppressing hippocampus ferroptosis via the Nrf2/GPX4 signaling pathway.

Automated summary

This study confirms the existence of ferroptosis in the pathogenesis of sepsis-associated encephalopathy (SAE) and demonstrates that irisin can attenuate cognitive dysfunction in SAE mice by inhibiting hippocampus ferroptosis. The protective effect of irisin is mediated through the Nrf2/GPX4 signaling pathway, which ameliorates the inflammatory microenvironment in SAE.