Microglia-derived CXCL2 induced neuronal ferroptosis via CXCR2/Jun axis in sepsis-associated encephalopathy.

Background: Neuronal ferroptosis is a characteristic pathological change of sepsis-associated encephalopathy (SAE), which can be induced by activated microglia. CXCL2 is mainly secreted by inflammatory cells (neutrophil and microglia) and involved in neuronal damage. However, the specific mechanism behind microglia-neuron crosstalk in SAE remains unclear.

Method: This study is to explore in which way microglia-secreted CXCL2 induced neuronal ferroptosis. For this purpose, the present study used CXCL2 knockdown (KD) mice to generate SAE model and determined effects of CXCL2 on neuronal ferroptosis. Afterward, BV2 and HT22 were used to instead of microglia and neuron respectively and the co-cultured system was used to simulate their interaction environment. RNA-sequencing technology was applied to investigate the key mechanism and targets of CXCL2-induced neuronal ferroptosis. siRNA was used to evaluate the function of key molecules.

Results: Cecum ligation perforation (CLP) induced an obvious cognitive dysfunction, shorten the survival time and promoted the activation of microglia and neuronal loss. The level of inflammatory cytokines, ferroptosis-related markers and malonaldehyde was obviously lower and the level of glutathione was significantly higher in CXCL2 KD mice when compared with wide-type SAE mice. RNA-seq revealed that Jun is a potential target of CXCL2. The following experiments further demonstrated that microglia-secreted CXCL2 induced the neuronal ferroptosis, but siRNA-Jun in neuron can abolish this effect. In addition, siRNA-CXCL2 of microglia mitigated the neuronal ferroptosis induced by sepsis, while Jun agonist reversed this protective effect.

Conclusion: In conclusion, microglia-derived CXCL2 could induce the occurrence of neuronal ferroptosis by targeting Jun. Thus, regulating the expression and secretion of CXCL2 will probably be a crucially novel strategy for the treatment of SAE.