Related Experiment Video
Updated: May 9, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglia-derived CXCL2 induced neuronal ferroptosis via CXCR2/Jun axis in sepsis-associated encephalopathy
Yu-Shen Yang1, Jin-Wei Liang1, Meng-Qin Pei1
1Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
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 in vivo 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.
Insights
Microglia-secreted CXCL2 drives neuronal ferroptosis in sepsis-associated encephalopathy by targeting Jun. Reducing CXCL2 may offer a novel therapeutic strategy for SAE.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Sepsis-associated encephalopathy (SAE) is characterized by neuronal ferroptosis, often induced by activated microglia.
- Chemokine (C-X-C motif) ligand 2 (CXCL2) secreted by inflammatory cells contributes to neuronal damage in SAE.
- The precise mechanisms of microglia-neuron communication in SAE remain incompletely understood.
Purpose of the Study:
- To elucidate the mechanism by which microglia-derived CXCL2 induces neuronal ferroptosis in SAE.
- To investigate the role of CXCL2 in the pathological changes associated with SAE.
- To identify key molecular targets involved in CXCL2-mediated neuronal damage.
Main Methods:
- Generation of a murine SAE model using cecum ligation perforation (CLP) and CXCL2 knockdown (KD) mice.
- Co-culture systems of BV2 (microglia) and HT22 (neuron) cells to mimic in vivo interactions.
- RNA-sequencing to identify molecular targets of CXCL2.
- Small interfering RNA (siRNA) and Jun agonist to validate molecular functions.
Main Results:
- CLP induced cognitive dysfunction, mortality, microglial activation, and neuronal loss in wild-type mice.
- CXCL2 KD mice exhibited reduced inflammatory cytokines, ferroptosis markers, and malondialdehyde, with increased glutathione levels.
- RNA-seq identified Jun as a key target; siRNA-Jun abolished CXCL2-induced neuronal ferroptosis, while Jun agonists reversed protective effects of siRNA-CXCL2.
Conclusions:
- Microglia-derived CXCL2 induces neuronal ferroptosis in SAE by targeting the Jun pathway.
- Targeting CXCL2 expression and secretion presents a promising therapeutic avenue for SAE treatment.
