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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1512300
This article is part of the Research Topic Crosstalk in Ferroptosis, Immunity & Inflammation View all 14 articles

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

Provisionally accepted
Yu-Shen Yang Yu-Shen Yang Jin-Wei Liang Jin-Wei Liang Meng-Qin Pei Meng-Qin Pei Yu-Ming Fang Yu-Ming Fang Zhen-Dong Sun Zhen-Dong Sun He-fan He He-fan He *
  • The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China

The final, formatted version of the article will be published soon.

    Background: Neuronal ferroptosis is a characteristic pathological change of sepsisassociated 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 microglianeuron 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.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.

    Keywords: sepsis-associated encephalopathy, neuronal ferroptosis, microglia activation, CXCL2/CXCR2 axis, crosstalk

    Received: 16 Oct 2024; Accepted: 17 Dec 2024.

    Copyright: © 2024 Yang, Liang, Pei, Fang, Sun and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: He-fan He, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China

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