FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury

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外文摘要：Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.Methods:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests.We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout mice.Results:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model.Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced depression.In the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high neutrophils.In the chronic stage,the"FOXO1-transferrin receptor(TFRC)"mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression after TBI.Conclusions:FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI,which provides insight into the heterogeneity,reprogramming activity,and versatility of neutrophils in TBI.

外文关键词：

Traumatic brain injury(TBI)NeutrophilForkhead box protein O1(FOXO1)Acute stageChronic stage

作者：

Mi Zhou、Yang-Wu-Yue Liu、Yu-Hang He、Jing-Yu Zhang、Hao Guo、Hao Wang、Jia-Kui Ren、Yi-Xun Su、Teng Yang、Jia-Bo Li、Wen-Hui He、Peng-Jiao Ma、Man-Tian Mi、Shuang-Shuang Dai

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作者单位：

Department of Biochemistry and Molecular Biology,School of Basic Medicine,Army Medical University,Chongqing 400038,China

Research Center for Nutrition and Food Safety,Chongqing Key Laboratory of Nutrition and Health,Institute of Military Preventive Medicine,Army Medical University,Chongqing 400038,China

Department of Neurosurgery,Daping Hospital,Army Medical University,Chongqing 400042,China

Department of Trauma and Emergency,Southwest Hospital,Army Medical University,Chongqing 400038,China

Department of Histology and Embryology,Chongqing Key Laboratory of Neurobiology,Brain and Intelligence Research Key Suyixun Laboratory of Chongqing Education Commission,Army Medical University,Chongqing 400038,China

Research Center,Seventh Affiliated Hospital of Sun Yat-Sen University,Shenzhen 518107,Guangdong,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaScience Fund for Creative Research Groups of Chongqing Municipal Education Commission of Chinagrants from the Talent Foundation of Army Medical UniversityScientific Research GrantChongqing Natural Science Foundation of China

项目编号：

8207177981901626ALJ22J003CSTB2022NSCQ-MSX0177

出版年：

2024

DOI：

10.1186/s40779-024-00523-w

军事医学研究(英文)

CSTPCD

ISSN：2095-7467

年,卷(期)：2024.11(4)